Diagnosis and treatment of arthritis using epigenetics

REFERENCE TO SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled UCSD055_—001A.TXT, created Aug. 24, 2012, which is approximately 135,386 KB in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

Embodiments of the present invention include methods, compositions and kits for evaluating a diagnosis, prognosis, or response to treatment of a subject with a disorder such as rheumatoid arthritis or osteoarthritis. Some embodiments include identifying a therapeutic agent for treating a disorder such as rheumatoid arthritis or osteoarthritis.

BACKGROUND OF THE INVENTION

Rheumatoid arthritis is an immune-mediated disease marked by symmetric inflammation in diarthrodial joints and destruction of the extracellular matrix. Genomics has rapidly advanced our understanding of susceptibility and severity of RA, and many associated polymorphisms in key genes have been described. However, identical twins have a concordance rate of only 12-15% suggesting that other influences can affect either the onset or progression of disease, such as epigenetic regulation of gene expression. One of the most widely studied epigenetic mechanisms, especially in oncology, is DNA methylation, which plays a key role regulating and silencing gene expression and could potentially contribute to immune dysregulation.

The pathogenesis of Rheumatoid arthritis (RA) is complex and involves numerous cell types that contribute through adaptive and innate immune responses (Firestein G S. Evolving concepts of rheumatoid arthritis. Nature, 423:356-361, 2003). Fibroblast-like synoviocytes (FLS), which form the synovial intimal lining, play an integral role by producing key cytokines (e.g., IL-6), small molecule mediators (e.g., prostanoids), and proteases (e.g., metalloproteinases). While osteoclasts are the primary effectors of bone erosions in arthritis, FLS are responsible for cartilage damage by virtue of their ability to adhere to and invade cartilage extracellular matrix. This capacity requires homotypic aggregation mediated by the adhesion molecule cadherin-11, which directs intimal lining formation and supports an invasive phenotype (Kiener H P et al. Cadherin 11 promotes invasive behavior of fibroblast-like synoviocytes. Arthritis Rheum. 2009 May; 60(5):1305-10). A well-defined relationship has long been recognized between synovial tissue histology and function and peripheral blood cell characteristics in diseases like RA, most likely because the circulating cells actively traffic between the synovium, lymph nodes, and peripheral blood (Malone D G et al. Immune function in severe, active rheumatoid arthritis. A relationship between peripheral blood mononuclear cell proliferation to soluble antigens and synovial tissue immunohistologic characteristics. J Clin Invest., 74(4):1173-1185, 1984; Firestein, G S. Etiology and pathogenesis of rheumatoid arthritis, In: Textbook of Rheumatology, G S Firestein, et al. eds., Elsevier, Philadelphia, 8th edition, 2009, pp. 1035-86). Understanding the precise molecular mechanisms that regulate FLS and peripheral blood cell activation in inflammatory arthritis could provide insights into the pathogenesis of RA and lead to novel therapeutic strategies.

SUMMARY OF THE INVENTION

Some embodiments also include comprising comparing the methylation states of the at least 2 loci or at least 2 genes in the sample from said subject with the methylation states of the loci or genes in normal tissue, tissue from a subject without said known rheumatoid arthritis or osteoarthritis prognosis, or tissue from a subject without said known response to treatment for rheumatoid arthritis or osteoarthritis.

In some embodiments, an increase or decrease in the extent of methylation of at least 2 loci or at least 2 genes compared to the extent of methylation of the loci or genes in normal tissue, tissue from a subject without said known rheumatoid arthritis or osteoarthritis prognosis, or tissue from a subject without said known response to treatment for rheumatoid arthritis or osteoarthritis is indicative of the presence or absence of rheumatoid arthritis, osteoarthritis, a rheumatoid arthritis or osteoarthritis prognosis, or response to treatment for rheumatoid arthritis or osteoarthritis for the subject.

In some embodiments, the methylation states of said at least 2 loci or at least 2 genes are determined in fibroblasts from said subject. In some embodiments, the methylation state of said at least 2 loci or at least 2 genes is determined in synoviocytes from said subject. In some embodiments, the methylation states of said at least 2 loci or at least 2 genes are determined in fibroblast-like synoviocytes from said subject. In some embodiments, the methylation states of said at least 2 loci or at least 2 genes are determined in rheumatoid arthritis fibroblast-like synoviocytes from said subject. In some embodiments, the methylation states of said at least 2 loci or at least 2 genes are determined in osteoarthritis fibroblast-like synoviocytes from said subject.

In some embodiments, the methylation states of said at least 2 loci or at least 2 genes are determined in macrophage from said subject.

In some embodiments, the methylation states of said at least 2 loci or at least 2 genes are determined in peripheral blood cells from said subject. In some embodiments, the peripheral blood cell is selected from the group consisting of white blood cell, neutrophil, eosinophil, basophil, lymphocyte, B cell, plasma cell, T cell, natural killer cell, monocyte, and dendritic cell.

In some embodiments, the sample is selected from the group consisting of a tissue sample, a frozen tissue sample, a biopsy specimen, a surgical specimen, a cytological specimen, whole blood, bone marrow, cerebral spinal fluid, peritoneal fluid, lymph fluid, serum, plasma, urine, stool, and nipple aspirate.

In some embodiments, the at least 2 loci are selected from the group consisting of SEQ ID NO.s 1-485512. In some embodiments, the at least 2 loci are selected from the group consisting of the loci listed in TABLE 6. In some embodiments, the at least 2 loci are selected from the group consisting of the loci listed in TABLE 7. In some embodiments, the at least 2 loci are selected from the group consisting of the loci listed in TABLE 8. In some embodiments, the at least 2 loci are selected from the group consisting of the loci listed in TABLE 3.

In some embodiments, the methylation states of at least 5 nucleic acid loci or at least 5 genes in said sample are determined. In some embodiments, the methylation states of at least 10 nucleic acid loci or at least 10 genes in said sample are determined. In some embodiments, the methylation states of at least 20 nucleic acid loci or at least 20 genes in said sample are determined. In some embodiments, the methylation states of at least 50 nucleic acid loci or at least 50 genes in said sample are determined. In some embodiments, the methylation states of at least 100 nucleic acid loci or at least 100 genes are determined.

In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

In some embodiments, the nucleic acid loci are selected from the group consisting of the loci listed in TABLE 6. In some embodiments, the nucleic acid loci are selected from the group consisting of the loci listed in TABLE 7. In some embodiments, the nucleic acid loci are selected from the group consisting of the loci listed in TABLE 8.

Some embodiments also include comparing the methylation state of the plurality of nucleic acid loci or the methylation state of the plurality of genes in the sample from said subject with the methylation state of the plurality of nucleic acid loci or the methylation state of the plurality of genes in normal tissue, tissue from a subject without said known rheumatoid arthritis or osteoarthritis prognosis, or tissue from a subject without said known response to treatment for rheumatoid arthritis or osteoarthritis.

In some embodiments, an increase or decrease in the extent of methylation of plurality of nucleic acid loci or of the methylation state of the plurality of genes compared to the extent of methylation of the plurality of nucleic acid loci or the extent of methylation of the plurality of genes in normal tissue, tissue from a subject without said known rheumatoid arthritis or osteoarthritis prognosis, or tissue from a subject without said known response to treatment for rheumatoid arthritis or osteoarthritis is indicative of the presence or absence of rheumatoid arthritis, osteoarthritis, a rheumatoid arthritis or osteoarthritis prognosis, or response to treatment for rheumatoid arthritis or osteoarthritis for the subject.

In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes is determined in fibroblasts from said subject. In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes is determined in synoviocytes from said subject. In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes is determined in fibroblast-like synoviocytes from said subject. In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes is determined in rheumatoid arthritis fibroblast-like synoviocytes from said subject. In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes is determined in osteoarthritis fibroblast-like synoviocytes from said subject.

In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes is determined in macrophage from said subject.

In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes is determined in peripheral blood cells from said subject. In some embodiments, the peripheral blood cell is selected from the group consisting of white blood cell, neutrophil, eosinophil, basophil, lymphocyte, B cell, plasma cell, T cell, natural killer cell, monocyte, and dendritic cell.

In some embodiments, the plurality of nucleic acid loci is selected from the group consisting of SEQ ID NO.s 1-485512. In some embodiments, the plurality of nucleic acid loci is selected from the group consisting of the loci listed in TABLE 6. In some embodiments, the plurality of nucleic acid loci is selected from the group consisting of the loci listed in TABLE 7. In some embodiments, the plurality of nucleic acid loci is selected from the group consisting of the loci listed in TABLE 8.

In some embodiments, the plurality genes is selected from the group consisting of the loci listed in TABLE 3.

In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

Some embodiments of the methods, compositions and kits provided herein include a method of identifying a methylation profile indicative of rheumatoid arthritis, osteoarthritis, a rheumatoid arthritis or osteoarthritis prognosis, or a response to treatment for rheumatoid arthritis or osteoarthritis comprising determining the methylation states of a plurality of nucleic acid loci or the methylation states of a plurality of genes in a sample from a test subject with rheumatoid arthritis, osteoarthritis, a particular rheumatoid arthritis or osteoarthritis prognosis, or a particular response to treatment for rheumatoid arthritis or osteoarthritis; determining the methylation states of said plurality of nucleic acid loci or said plurality of genes in a sample from a control subject without rheumatoid arthritis, without osteoarthritis, without said rheumatoid arthritis or osteoarthritis prognosis or without said response to treatment for rheumatoid arthritis or osteoarthritis; and identifying loci or genes which are hypermethylated or hypomethylated in said sample from said test subject relative to said sample from said control subject to identify said methylation profile indicative of rheumatoid arthritis, osteoarthritis a rheumatoid arthritis or osteoarthritis prognosis, or a response to treatment for rheumatoid arthritis or osteoarthritis.

Some embodiments also include storing data representing said loci or said genes which are hypermethylated or hypomethylated in said sample from said test subject relative to said sample from said control subject on a non-transitory computer readable medium.

Some embodiments also include comparing the methylation states of a plurality of nucleic acid loci or the methylation states of a plurality of genes in a sample from a test subject with rheumatoid arthritis, osteoarthritis, a particular rheumatoid arthritis or osteoarthritis prognosis, or a particular response to treatment for rheumatoid arthritis or osteoarthritis with the methylation states of said plurality of nucleic acid loci or the methylation states of said plurality of genes in a sample from a control subject without rheumatoid arthritis, without osteoarthritis, without said rheumatoid arthritis or osteoarthritis prognosis or without said response to treatment for rheumatoid arthritis or osteoarthritis.

In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes in a sample from said test subject or said control subject is determined in fibroblasts from said test subject or said control subject. In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes in a sample from said test subject or said control subject is determined in synoviocytes from said test subject or said control subject. In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes in a sample from said test subject or control subject is determined in fibroblast-like synoviocytes from said test subject or said control subject. In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes in a sample from said test subject or control subject is determined in rheumatoid arthritis fibroblast-like synoviocytes from said test subject or control subject. In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes in a sample from said test subject or control subject is determined in osteoarthritis fibroblast-like synoviocytes from said test subject or control subject.

In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes in a sample from said test subject or control subject is determined in macrophage from said test subject or control subject.

In some embodiments, the methylation state of said plurality of nucleic acid loci or said plurality of genes in a sample from said test subject or control subject is determined in peripheral blood cells from said test subject or control subject. In some embodiments, the peripheral blood cell is selected from the group consisting of white blood cell, neutrophil, eosinophil, basophil, lymphocyte, B cell, plasma cell, T cell, natural killer cell, monocyte, and dendritic cell.

In some embodiments, the methylation states of at least 5 nucleic acid loci or at least 5 genes are determined. In some embodiments, the methylation states of at least 10 nucleic acid loci or at least 10 genes are determined. In some embodiments, the methylation states of at least 20 nucleic acid loci or at least 20 genes are determined. In some embodiments, the methylation states of at least 50 nucleic acid loci or at least 50 genes are determined. In some embodiments, the methylation states of at least 100 nucleic acid loci or at least 100 genes are determined.

In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

Some embodiments of the methods, compositions and kits provided herein include a method for diagnosing rheumatoid arthritis or osteoarthritis, determining a rheumatoid arthritis or osteoarthritis prognosis, or determining or predicting a response to treatment for rheumatoid arthritis or osteoarthritis in a subject comprising accessing first data representing the methylation status of nucleic acid loci or the methylation status of at least one gene which are differentially methylated in individuals with rheumatoid arthritis, osteoarthritis a rheumatoid arthritis or osteoarthritis prognosis, or a response to treatment for rheumatoid arthritis or osteoarthritis wherein said data is stored on a non-transitory computer readable medium; instructing a computer to compare said first data to second data representing the methylation status of said nucleic acid loci or said at least one gene in a sample taken from said subject, wherein said data representing the methylation status of said nucleic acid loci or said at least one gene in a sample taken from said subject is stored on a non-transitory computer readable medium; and instructing said computer to provide an output indicating whether said comparison indicates that said subject has rheumatoid arthritis or osteoarthritis, has a positive or negative prognosis for rheumatoid arthritis or osteoarthritis prognosis, or indicates a positive or negative prediction for the subject's response to treatment for rheumatoid arthritis or osteoarthritis.

Some embodiments also include diagnosing rheumatoid arthritis or osteoarthritis, determining a rheumatoid arthritis or osteoarthritis prognosis, or determining or predicting a response to treatment for rheumatoid arthritis or osteoarthritis in said subject if said first data representing the methylation status of said nucleic acid loci or said at least one gene in a sample taken from said subject are significantly similar to said second data representing nucleic acid loci or genes which are differentially methylated in individuals with rheumatoid arthritis, osteoarthritis a rheumatoid arthritis or osteoarthritis prognosis, or a response to treatment for rheumatoid arthritis or osteoarthritis.

Some embodiments also include comparing the methylation states of the at least 2 loci in the sample with the methylation states of the loci in normal tissue, tissue from a subject with a known prognosis, or tissue from a subject with a known response to treatment.

In some embodiments, an increase or decrease in the extent of methylation of at least 2 loci compared to the extent of methylation of the loci in normal tissue, tissue from a subject with a known prognosis, or tissue from a subject with a known response to treatment is indicative of the presence or absence of rheumatoid arthritis, prognosis, or response to treatment for the subject.

In some embodiments, the methylation states of said at least 2 loci are determined in fibroblasts from said subject. In some embodiments, the methylation states of said at least 2 loci are determined in synoviocytes from said subject. In some embodiments, the methylation states of said at least 2 loci are determined in fibroblast-like synoviocytes from said subject. In some embodiments, the methylations state of said at least 2 loci are determined in rheumatoid arthritis fibroblast-like synoviocytes from said subject. In some embodiments, the methylation states of said at least 2 loci are determined in osteoarthritis fibroblast-like synoviocytes from said subject.

In some embodiments, the methylation states of said at least 2 loci are determined in macrophage from said subject.

In some embodiments, the methylation states of said at least 2 loci are determined in peripheral blood cells from said subject. In some embodiments, the peripheral blood cell is selected from the group consisting of white blood cell, neutrophil, eosinophil, basophil, lymphocyte, B cell, plasma cell, T cell, natural killer cell, monocyte, and dendritic cell.

In some embodiments, the at least 2 loci are selected from the group consisting of the loci listed in TABLE 6. In some embodiments, the at least 2 loci are selected from the group consisting of the loci listed in TABLE 7. In some embodiments, the at least 2 loci are selected from the group consisting of the loci listed in TABLE 8. In some embodiments, the methylation states of at least 5 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8 are determined. In some embodiments, the methylation states of at least 10 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8 are determined. In some embodiments, the methylation states of at least 20 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8 are determined. In some embodiments, the methylation states of at least 50 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8 are determined. In some embodiments, the methylation states of at least 100 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8 are determined.

In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

Some embodiments of the methods, compositions and kits provided herein include a method for identifying a therapeutic agent for treating rheumatoid arthritis or osteoarthritis comprising contacting a cell with a test agent; and determining the methylation states in the contacted cell of at least 2 loci which have differential extents of methylation in individuals with rheumatoid arthritis or osteoarthritis relative to individuals without rheumatoid arthritis or osteoarthritis.

Some embodiments also include comparing the methylation states of the at least 2 loci in the contacted cell with the methylation states of the loci in a cell which was not contacted with the test agent; and selecting a test agent that increases or decreases the extent of methylation of the at least 2 loci in the cell contacted with the test agent compared to the extent of methylation of the at least 2 loci in a cell which was not contacted with the test agent such that the extent of methylation of the at least 2 loci in the cell contacted with the test agent is a methylation states associated with the absence of rheumatoid arthritis or osteoarthritis or with a reduction in the symptoms associated with rheumatoid arthritis osteoarthritis.

In some embodiments, the methylation states of at least 5 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8 are determined. In some embodiments, the methylation states of at least 10 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8 are determined. In some embodiments, the methylation states of at least 20 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8 are determined. In some embodiments, the methylation states of at least 50 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8 are determined. In some embodiments, the methylation states of at least 100 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8 are determined.

In some embodiments, the cell comprises a fibroblast. In some embodiments, the cell comprises a synoviocyte. In some embodiments, the cell comprises a fibroblast-like synoviocyte. In some embodiments, the cell comprises a rheumatoid arthritis fibroblast-like synoviocyte. In some embodiments, the cell comprises an osteoarthritis fibroblast-like synoviocyte.

In some embodiments, the cell comprises a macrophage.

In some embodiments, the cell comprises a peripheral blood cell. In some embodiments, the peripheral blood cell is selected from the group consisting of white blood cell, neutrophil, eosinophil, basophil, lymphocyte, B cell, plasma cell, T cell, natural killer cell, monocyte, and dendritic cell.

In some embodiments, the cell is mammalian. In some embodiments, the cell is a human.

In some embodiments, a sample comprises the cell, the sample selected from the group consisting of a tissue sample, a frozen tissue sample, a biopsy specimen, a surgical specimen, a cytological specimen, whole blood, bone marrow, cerebral spinal fluid, peritoneal fluid, lymph fluid, serum, plasma, urine, stool, and nipple aspirate.

Some embodiments of the methods, compositions and kits provided herein include a kit for diagnosing rheumatoid arthritis or osteoarthritis, determining a rheumatoid arthritis or osteoarthritis prognosis, or determining or predicting a response to treatment for rheumatoid arthritis or osteoarthritis in a subject comprising: a reagent for determining the methylation states of at least 2 loci which have differential extents of methylation in individuals with rheumatoid arthritis or osteoarthritis relative to individuals without rheumatoid arthritis or osteoarthritis.

Some embodiments also include at least one polynucleotide primer comprising a sequence hybridizing to at least a portion of the at least 2 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8.

In some embodiments, the reagent comprises a restriction enzyme.

In some embodiments, the at least 2 loci are selected from the group consisting of the loci listed in TABLE 6. In some embodiments, the at least 2 loci are selected from the group consisting of the loci listed in TABLE 7. In some embodiments, the at least 2 loci are selected from the group consisting of the loci listed in TABLE 7. In some embodiments, the reagent can determine the methylation states of at least 5 loci selected from the group consisting of SEQ ID NO.s 1-485512. In some embodiments, the reagent can determine the methylation states of at least 5 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8. In some embodiments, the reagent can determine the methylation states of at least 10 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8. In some embodiments, the reagent can determine the methylation states of at least 20 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8. In some embodiments, the reagent can determine the methylation states of at least 50 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8. In some embodiments, the reagent can determine the methylation states of at least 100 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8.

Some embodiments of the methods, compositions and kits provided herein include a method for determining whether an individual suffers from rheumatoid arthritis or osteoarthritis comprising determining the methylation states of at least 2 loci which have differential extents of methylation in individuals with rheumatoid arthritis or osteoarthritis relative to individuals without rheumatoid arthritis or osteoarthritis, wherein the individual is diagnosed with rheumatoid arthritis if the methylation state of said at least 2 loci are associated with rheumatoid arthritis and the individual is diagnosed with osteoarthritis if the methylation states of said at least 2 loci are associated with osteoarthritis.

Some embodiments also include comparing the methylation states of the at least 2 genes in the sample with the methylation states of the genes in normal tissue, tissue from a subject with a known prognosis, or tissue from a subject with a known response to treatment.

In some embodiments, an increase or decrease in the extent of methylation of at least 2 genes compared to the extent of methylation of the of the genes in normal tissue, tissue from a subject with a known prognosis, or tissue from a subject with a known response to treatment is indicative of the presence or absence of rheumatoid arthritis, prognosis, or response to treatment for the subject.

In some embodiments, the methylation states of said at least 2 loci are determined in fibroblasts from said subject. In some embodiments, the methylation states of said at least 2 loci are determined in synoviocytes from said subject. In some embodiments, the methylation states of said at least 2 loci are determined in fibroblast-like synoviocytes from said subject. In some embodiments, the methylation states of said at least 2 loci are determined in rheumatoid arthritis fibroblast-like synoviocytes from said subject. In some embodiments, the methylation states of said at least 2 loci are determined in osteoarthritis fibroblast-like synoviocytes from said subject.

In some embodiments, the methylation states of said at least 2 loci are determined in macrophage from said subject.

In some embodiments, the methylation states of at least 5 genes selected from the group consisting of the genes listed in TABLE 3 are determined. In some embodiments, the methylation states of at least 10 genes selected from the group consisting of the genes listed in TABLE 3 are determined. In some embodiments, the methylation states of at least 20 genes selected from the group consisting of the genes listed in TABLE 3 are determined. In some embodiments, the methylation states of at least 50 genes selected from the group consisting of the genes listed in TABLE 3 are determined.

In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

Some embodiments also include comparing the methylation states of the at least 2 genes in the contacted cell with the methylation states of the genes in a cell which was not contacted with the test agent; and selecting a test agent that increases or decreases the extent of methylation of the at least 2 genes in the cell contacted with the test agent compared to the extent of methylation of the at least 2 genes in a cell which was not contacted with the test agent such that the extent of methylation of the at least 2 genes in the cell contacted with the test agent is a methylation states associated with the absence of rheumatoid arthritis or osteoarthritis or with a reduction in the symptoms associated with rheumatoid arthritis or osteoarthritis.

In some embodiments, the cell comprises a macrophage.

In some embodiments, the cell is mammalian. In some embodiments, the cell is a human.

Some embodiments of the methods, compositions and kits provided herein include a kit for diagnosing rheumatoid arthritis or osteoarthritis, determining a rheumatoid arthritis or osteoarthritis prognosis, or determining or predicting a response to treatment for rheumatoid arthritis or osteoarthritis in a subject comprising: a reagent for determining the methylation states of at least 2 genes selected from the group consisting of the genes listed in TABLE 3.

Some embodiments also include at least one polynucleotide primer comprising a sequence hybridizing to at least a portion of the at least 2 genes selected from the group consisting of the genes listed in TABLE 3.

In some embodiments, the reagent comprises a restriction enzyme.

In some embodiments, the reagent can determine the methylation states of at least 5 genes selected from the group consisting of the genes listed in TABLE 3. In some embodiments, the reagent can determine the methylation states of at least 10 genes selected from the group consisting of the genes listed in TABLE 3. In some embodiments, the reagent can determine the methylation states of at least 20 genes selected from the group consisting of the genes listed in TABLE 3. In some embodiments, the reagent can determine the methylation states of at least 50 genes selected from the group consisting of the genes listed in TABLE 3.

Some embodiments of the methods, compositions and kits provided herein include a method for identifying a therapeutic agent for treating rheumatoid arthritis or osteoarthritis comprising contacting a cell with a test agent; and determining the methylation states of at least 2 genes selected from a gene encoding a protein that acts in a pathway that includes a protein encoded by a gene that is differentially methylated in a rheumatoid arthritis cell or that is differentially methylated in a osteoarthritis cell compared to a normal cell.

Some embodiments also include comparing the methylation states of the at least 2 genes in the contacted cell with the methylation states of the genes in a cell which was not contacted with the test agent; and selecting a test agent that increases or decreases the extent of methylation of the at least 2 genes in the cell contacted with the test agent compared to the extent of methylation of the at least 2 genes in a cell which was not contacted with the test agent such that the extent of methylation of the at least 2 genes in the cell contacted with the test agent are methylation states associated with the absence of rheumatoid arthritis or methylation states associated with the absence of osteoarthritis with a reduction in the symptoms associated with rheumatoid arthritis.

In some embodiments, the pathway is selected from the group consisting of the pathways listed in TABLE 5.

In some embodiments, the methylation states of at least 5 genes selected from genes encoding proteins that act in a pathway that includes a protein encoded by a gene that is differentially methylated in a rheumatoid arthritis cell compared to a normal cell or that is differentially methylated in a osteoarthritis cell compared to a normal cell. In some embodiments, the methylation states of at least 10 genes selected from genes encoding proteins that act in a pathway that includes a protein encoded by a gene that is differentially methylated in a rheumatoid arthritis cell compared to a normal cell or that is differentially methylated in a osteoarthritis cell compared to a normal cell.

In some embodiments, the cell comprises a macrophage.

In some embodiments, the cell is mammalian. In some embodiments, the cell is a human.

Some embodiments of the methods, compositions and kits provided herein include a method for identifying therapeutic agents for treating rheumatoid arthritis or osteoarthritis comprising contacting a cell with a test agent; and determining the activity of a protein encoded by a gene differentially methylated in a rheumatoid arthritis cell or that is differentially methylated in an osteoarthritis cell compared to a normal cell.

Some embodiments also include comparing the activity of the protein in the contacted cell with the activity of the protein in a cell which was not contacted with the test agent; and selecting a test agent that increases or decreases the activity of protein in the cell contacted with the test agent compared to the activity of the protein in a cell which was not contacted with the test agent such that the activity of the protein in the cell contacted with the test agent is an activity associated with the absence of rheumatoid arthritis or an activity associated with the absence of osteoarthritis with a reduction in the symptoms associated with rheumatoid arthritis.

In some embodiments, the protein is encoded by a gene selected from the group consisting of the genes listed in TABLE 3.

In some embodiments, the cell comprises a macrophage.

In some embodiments, the cell comprises a peripheral blood cell. In some embodiments, the peripheral blood cell is selected from the group consisting of white blood cell, including neutrophil, eosinophil, basophil, lymphocyte, B cell, plasma cell, T cell, natural killer cell, monocyte, and dendritic cell.

In some embodiments, the cell is mammalian. In some embodiments, the cell is a human.

Some embodiments of the methods, compositions and kits provided herein include a method of determining the methylation status of a plurality of human nucleic acid loci comprising contacting a nucleic acid sample from a human subject with a reagent capable of providing an indication of the methylation status of said loci, wherein said loci comprise at least 5 which have differential extents of methylation in individuals with rheumatoid arthritis or osteoarthritis relative to individuals without rheumatoid arthritis or osteoarthritis.

In some embodiments, said reagent is a restriction enzyme.

In some embodiments, said reagent is a primer.

In some embodiments, said reagent is a probe.

In some embodiments, said reagent comprises sodium bisulfate.

In some embodiments, the at least 5 loci are selected from the group consisting of SEQ ID NO.s 1-485512. In some embodiments, the at least 5 loci are selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8.

Some embodiments of the methods, compositions and kits provided herein include a nucleic acid array consisting essentially of nucleic acids useful for diagnosing rheumatoid arthritis or osteoarthritis, determining a prognosis of rheumatoid arthritis or osteoarthritis, or determining or predicting a response to treatment of a subject being evaluated for or suffering from rheumatoid arthritis or osteoarthritis, wherein said nucleic acids comprise at least 5 loci which have differential extents of methylation in individuals with rheumatoid arthritis or osteoarthritis relative to individuals without rheumatoid arthritis or osteoarthritis.

In some embodiments, said nucleic acids comprise at least 5 loci selected from the group consisting of SEQ ID NO.s 1-485512. In some embodiments, said nucleic acids comprise at least 5 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8. In some embodiments, said nucleic acids comprise at least 10 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8. In some embodiments, said nucleic acids comprise at least 20 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8. In some embodiments, said nucleic acids comprise at least 50 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, and TABLE 8.

Some embodiments of the methods, compositions and kits provided herein include a method of ameliorating rheumatoid arthritis or osteoarthritis comprising evaluating the methylation status of a plurality of human nucleic acid loci in a nucleic acid sample from a human subject having symptoms of rheumatoid arthritis or osteoarthritis, wherein said loci comprise at least 5 loci which have differential extents of methylation in individuals with rheumatoid arthritis or osteoarthritis relative to individuals without rheumatoid arthritis or osteoarthritis; and administering a treatment for rheumatoid arthritis or osteoarthritis if said at least 5 loci have a methylation status indicative of rheumatoid arthritis or osteoarthritis.

Some embodiments of the methods, compositions and kits provided herein include a mixture comprising a plurality of human nucleic acid loci from a human subject having symptoms indicative of potential rheumatoid arthritis or osteoarthritis and a reagent capable of providing an indication of the methylation status of said loci, wherein said loci comprise at least 5 loci which have differential extents of methylation in individuals with rheumatoid arthritis or osteoarthritis relative to individuals without rheumatoid arthritis or osteoarthritis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts DNA methyltranserases (DNMTs) function. DNMTs transfer methyl groups from SAM to deoxycytodine. DNMT function can be affected by changes in methyl donors in the diet or by DNMT inhibitors, like 5-aza-2′-deoxycytidine (5-azaC). The analog 5-azacytidine is also incorporated into RNA and can interfere with many other cellular processes.

FIG. 2 depicts an ILLUMINA array analysis of DNA methylation in RA and OA FLS, and the hierarchical clustering and heatmap of differentially methylated loci. The methylation levels at the 1,859 significantly differentially methylated loci were used for hierarchical clustering. The clustering of the sample is shown by the dendrogram at the top and the clustering of the loci is shown by the dendrogram on the left. The methylation levels at the loci are shown in the heatmap.

FIG. 3 depicts hypomethylation of several genes in RA FLS basal expression compared to OA FLS. Gene expression was determined by PCR in 6 to 13 separate OA and RA FLS lines for 7 genes that were significantly hypomethylated (CHI3L1, COL1A1, MYEF2, ITG4A, SYNJ2, STK24, MAP3K5). As a group, expression of hypomethylated genes in RA was significantly greater than OA (P<0.01); expression of genes that were normally methylated in RA was similar to OA, e.g., AXIN, IKKE, TBK1, NANOG, POU5F1, MAP2K6, IRF3.

FIG. 4 depicts an analysis of the focal adhesion pathway, with differentially methylated genes (ECM=extracellular matrix). Differentially methylated genes are present in key locations, most notably RTK, ITGA and ITGB.

FIG. 5 depicts a Cytoscape analysis to evaluate the networks affected by differential methylation and determine the most likely targets for subsequent analysis.

FIG. 6 depicts basal expression of DNMTs. DNMT expression was examined in resting cultured FLS. Synoviocytes were isolated from RA and OA synovium at the time of total joint replacement. 4^ththrough 6^thpassage cells were evaluated by qPCR (graph shows relative expression units using the standard curve method).

FIG. 7 depicts decreased DNMT1 gene expression after IL-1 stimulation. FLS were stimulated with IL-1 for 24 hr and DNMT expression was determined by qPCR.

FIG. 8 depicts the decrease in DNMT function in FLS in response to IL-1. FLS were stimulated with 1 ng/ml of IL-1 for 14 days and extracts were assayed using the DNMT Activity/Inhibition Assay (Active Motif Co., Carlsbad, Calif.), which is an ELISA-based method that measures methylation of a CpG-enriched DNA substrate. A significant decline in total DNMT function (p<0.05) was observed.

DETAILED DESCRIPTION

Abnormalities in DNA methylation have been implicated in autoimmunity. The mechanism of the aggressive rheumatoid phenotype is uncertain, although several studies implicate abnormal tumor suppressor gene structure and function. Differential DNA methylation might lead to altered gene expression, synoviocyte function, and peripheral blood cell function. Global DNA methylation patterns in RA FLS were evaluated and compared to FLS derived from individuals with non-inflammatory joint disease. The data show that the RA FLS display a DNA methylome signature that distinguishes them from osteoarthritis (OA) FLS, with differentially methylated genes that are critical to cell trafficking, inflammation, and cell-extracellular matrix interactions. This signature could define risk factors for developing RA or represent imprinting due to the synovial milieu. A relationship exists between the immunopathologic status of the synovial milieu and peripheral blood mononuclear cell immune function (See e.g., Malone, et al., J Clin Invest., 74(4):1173-1185, 1984; Firestein, G S. Etiology and pathogenesis of rheumatoid arthritis, In: Textbook of Rheumatology, G S Firestein, et al. eds., Elsevier, Philadelphia, 8th edition, 2009, pp. 1035-86). Peripheral blood mononuclear cells in patients with rheumatoid arthritis demonstrate global methylation abnormalities that parallel those found in cultured fibroblast-like synoviocytes, confirming that peripheral blood cells reflect synovial biology and synoviocyte function. Methylation of the IL-10 promoter has been studied in patients with RA (Fu L. H. et al., Methylation status of the IL-10 gene promoter in the peripheral blood mononuclear cells of rheumatoid arthritis patients. Yi Chuan. 2007 November; 29(11):1357-61). However, no previous data has identified patterns of specific combinations of loci or a distinctive methylome signature that can be used to diagnose RA or provide information on the potential response to therapy (Liu C C, et al. Global DNA methylation, DNMT1, and MBD2 in patients with rheumatoid arthritis. Immunol Lett. 2011; 135:96-9; Karouzakis E, et al. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2009; 60:3613-22).

Data implicating low DNA methylation in FLS is especially intriguing in the context of RA, where pathogenic FLS exhibit many features of partially transformed cells. DNMT regulation and the methylation status of FLS were examined in view of the association of DNA hypomethylation and an aggressive phenotype in cancer. As shown in this application, differences in basal RA vs. OA DNMT expression previously described were not confirmed. This may have been because conditions in the examples of this application were rigorously controlled by discontinuing methotrexate treatment up to a month before surgery. Furthermore, it was found that IL-1 significantly decreased DNMT1, DNMT3a, and DNMT3b gene expression within hours. The change in DNMT expression was accompanied by decreased DNMT function in nuclear extracts and global hypomethylation. More striking, as described in this application, an ILLUMINA methylation array study of RA and OA cells showed 100% concordance between DNA methylation patterns and the presence of RA, indicating that RA cells are imprinted with a distinctive methylation pattern that contributes to the pathogenesis of disease.

The unique pattern of DNA methylation in RA or OA, either taken in toto or when considered based on individual loci, genes, or pathways with differential methylation, has several implications. The pattern can be used for several applications, including: diagnosis of RA or OA; assessment of disease activity and prognosis of RA or OA; identification of novel therapeutic targets useful for the development of novel therapies for RA or OA; and the development of novel therapies that increase or decrease DNA methylation and alter the pattern, such as through DNMT inhibitors or activators.

Like peripheral blood mononuclear cells, rheumatoid FLS exhibit an abnormal phenotype that contributes to disease pathogenesis (Firestein, G S. Invasive fibroblast-like synoviocytes in rheumatoid arthritis: Passive responders or transformed aggressors? Arthritis Rheum 39:1781-1790, 1996). Functional studies suggest that RA FLS are imprinted in situ and maintain these features after many passages in tissue culture. For example, RA FLS, unlike OA or normal synoviocytes, adhere to and invade cartilage explants in SCID mice (Müller-Ladner U et al. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J. Pathol. 1996 November; 149(5):1607-15). RA FLS can grow under anchorage-independent conditions and are less susceptible to contact inhibition. Apoptosis of RA synoviocytes in situ appears to be defective, which contributes to intimal lining hyperplasia (Baier A et al. Apoptosis in rheumatoid arthritis. Curr Opin Rheumatol. 2003 May; 15(3):274-9). Data in a SCID mouse model show that RA synoviocytes can migrate from one site to another, thereby serving as a mechanism to spread the RA phenotype and cartilage damage to distant joints (Lefèvre S et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 2009 December; 15(12):1414-20). Despite these findings, RA FLS are not truly transformed, as they senesce in culture after 10 to 15 passages.

Several mechanisms have been implicated in the rheumatoid phenotype. For instance, resistance to apoptosis can be due, in part, to defective expression of Phosphatase and tensin homolog (PTEN) expression, high levels of sentrin, or preferential shunting of stressed cells to DNA repair rather than programmed cell death (Pap T et al. Activation of synovial fibroblasts in rheumatoid arthritis: lack of Expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthritis Res. 2000; 2(1):59-64; Franz J K et al. Expression of sentrin, a novel antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis. Arthritis Rheum. 2000 March; 43(3):599-607; and You X et al. PUMA-mediated apoptosis in fibroblast-like synoviocytes does not require p53. Arthritis Res Ther. 2006; 8(6):R157). Somatic mutations of regulatory genes have been identified in cultured FLS, including the p53 tumor suppressor gene (Firestein G S et al. Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proc Natl Acad Sci USA, 94: 10895-10900, 1997; Igarashi H et al. TP53 mutations coincide with the ectopic expression of activation-induced cytidine deaminase in the fibroblast-like synoviocytes derived from a fraction of patients with rheumatoid arthritis. Clin Exp Immunol. 2010 Jul. 1; 161(1):71-80; Inazuka M et al. Analysis of p53 tumour suppressor gene somatic mutations in rheumatoid arthritis synovium. Rheumatology (Oxford). 2000 March; 39(3):262-6; and Rème T et al. Mutations of the p53 tumour suppressor gene in erosive rheumatoid synovial tissue. Clin Exp Immunol. 1998 February; 111(2):353-8). Similar somatic mutations have also been described in peripheral blood mononuclear cells and synovial cells, confirming that these cell populations share many structural DNA characteristics that are either caused by RA or a result of the toxic synovial microenvironment (Cannons J L, et al. HPRT-mutant T cells in the peripheral blood and synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum. 1998; 41:1772-82).

The abnormal cells are more invasive and produce increased amounts of cytokines and metalloproteinases. Microdissection of rheumatoid synovium shows islands of mutant cells residing in the intimal lining that produce prodigious amount of IL-6 (Yamanishi Y et al. p53 regulates apoptosis, synovitis and joint destruction in collagen-induced arthritis. Amer J Pathol, 160:123-30, 2002). Microsatellite instability has also been identified in RA synovium, in part due to decreased DNA repair function (Lee S—H et al. Microsatellite instability and suppressed DNA repair enzyme expression in rheumatoid arthritis. J Immunol, 170:2214-20, 2003). Somatic mutations in several other genes, including mitochondrial DNA and structural proteins like vimentin, have also been reported (Bang H et al. Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum. 2007 August; 56(8):2503-11; Da Sylva T R et al. Somatic mutations in the mitochondria of rheumatoid arthritis synoviocytes. Arthritis Res Ther. 2005; 7(4):R844-51). Most of these and other aggressive features appear to be result of imprinting by rheumatoid synovial environment. Thus, they serve as amplifying mechanisms that alters the natural history of disease and enhance extracellular matrix destruction and cytokine production, leading to a signature in the systemic circulation due to cellular trafficking that can be detected in peripheral blood cells, for example.

While the focus on gene sequences, mutations, and aggressive behavior has provided useful information, other mechanisms can change cell phenotype. Epigenetics, for instance, can profoundly influence cell activation and gene expression and include DNA methylation, histone modification, and microRNAs. Histone acetylation by histone acetyltransferases (HATs) can remodel chromatin and enhance gene expression while deacetylation by histone deacetylases (HDACs) has the opposite effect. The histone deacetylase HDAC1 is overexpressed in RA FLS and HDAC inhibitors decrease synoviocyte proliferation in culture and joint damage in collagen-induced arthritis (Horiuchi M et al. Expression and function of histone deacetylases in rheumatoid arthritis synovial fibroblasts. J. Rheumatol. 2009 August; 36(8):1580-9; Saouaf S J et al. Deacetylase inhibition increases regulatory T cell function and decreases incidence and severity of collagen-induced arthritis. Exp Mol Pathol. 2009; 87(2):99-104). MicroRNAs are another epigenetic mechanism that contribute to DNA accessibility and chromatin remodeling by directly targeting individual genes. Expression of some individual microRNAs like microRNA-124a, are decreased in RA compared with OA cells, leading to enhanced chemokine expression (Nakamachi Y et al. MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum 60:1294, 2009; Stanczyk J et al. Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum. 2011 February; 63 (2): 373-81).

DNA methylation is especially relevant to RA in terms of epigenetic mechanisms by virtue of its role in neoplasia as well as embryonic growth and development. Normal ontogeny relies on a carefully orchestrated sequence of DNA methylation to repress regulatory genes by methylating cytosine in CpG islands after they have completed their programmed role in early development (Christophersen N S and Helin K. Epigenetic control of embryonic stem cell fate. J Exp Med. Oct. 25, 2010; 207(11):2287-95). Methylation abnormalities have been associated with a variety of diseases, most notably cancer where hypomethylation and renewed expression of embryonic genes can allow cells to de-differentiate and escape from normal homeostatic controls (Kulis M and Esteller M. DNA methylation and cancer. Adv Genet. 2010; 70:27-56). Hypermethylation has also been associated with certain malignancies (Ren J et al. DNA hypermethylation as a chemotherapy target. Cell Signal. Feb. 21, 2011).

DNA methyltransferases (DNMTs) are responsible for initiating and maintaining CpG methylation in the human genome by converting cytosine to methylcytosine (FIG. 1) (Turek-Plewa J and Jagodzinski P P. The role of mammalian DNA methyltransferases in the regulation of gene expression. Cell Mol Biol Lett. 2005; 10(4):631-47). In mammalian cells, DNMT1, DNMT3a, and DNMT3b are the primary enzymes responsible for CpG methylation. DNMT3a and DNMT3b mainly regulate de novo methylation while DNMT1 maintains methylation, especially during cell division. Thus, DNMT1 plays a greater role perpetuating methylation patterns in proliferating cells. Decreased DNMT expression is associated with global hypomethylation as well as suppressed methylation of individual genes that participate in malignant transformation (Shukla V et al. BRCA1 affects global DNA methylation through regulation of DNMT1. Cell Res. 2010 November; 20(11):1201-15). DNMT expression and DNA methylation is not fixed but can be influenced by the environment and modify gene expression throughout life. The DNMTs can also maintain the methylation pattern during cell division, thereby allowing daughter cells to reflect the environmental influences of the parent cells.

DNMTs can also permit vertical transmission of parental DNA methylation (Ko Y G et al. Stage-by-stage change in DNA methylation status of Dnmt1 locus during mouse early development. J Biol. Chem. 2005 Mar. 11; 280(10):9627-34). This process allows relatively rapid responses to environmental stress that can persist over many cell divisions and even across generations (Rosenfeld. Animal models to study environmental epigenetics. Biol Reprod. 2010, 82:473-88; Kaati G et al. Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet. 2007 July; 15(7):784-90). For instance, pregnant mice fed a diet rich in methyl donors like folate have increased levels of DNA methylation for at least 2 subsequent generations. Methylation of the Runx3 gene, in particular, is increased by the high methyl donor diet and leads to enhanced Th2 lymphocyte differentiation and increased airway reactivity in murine asthma (Hollingsworth J W et al. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest. 2008 October; 118(10):3462-9). Increased disease severity and airway remodeling can even be observed in F2 progeny and demonstrates how the environment can have multigenerational effects (Miller R L. Prenatal maternal diet affects asthma risk in offspring. J Clin Invest. 2008. 118:3265-8).

Abnormalities in DNA methylation have been implicated in autoimmunity. In addition to the murine model of airway disease, T cells can be affected by DNA methylation and influence Th2 differentiation (Gamper C J et al. Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation. J Immunol. 2009 Aug. 15; 183(4):2267-76). The DNMT inhibitor 5′-aza-2′-deoxycytidine (5-azaC) (Fandy T E. Development of DNA methyltransferase inhibitors for the treatment of neoplastic diseases. Curr Med. Chem. 2009; 16(17):2075-85) affects expression of many T cell genes, including IFNα, IL-4, CD70, and LFA-1. 5-azaC enhances autoreactivity and induces robust responses to normally sub-threshold stimulation (Richardson B. DNA methylation and autoimmune disease. Clin Immunol. 2003 October; 109(1):72-9). T and B cell interactions are also affected, in part due to altered expression of surface receptors like CD70 (Oelke K et al. Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors. Arthritis Rheum. 2004 June; 50(6):1850-60). Decreased DNA methylation in Th1 and Th2 cell genomic DNA is also associated with production of anti-dsDNA antibodies in vivo (Richardson B et al. Murine models of lupus induced by hypomethylated T cells. Methods Mol Med. 2004; 102:285-94). Hypomethylation has been described in peripheral blood mononuclear cells in patients with RA (Liu C C et al. Global DNA methylation, DNMT1, and MBD2 in patients with rheumatoid arthritis. Immunol Lett. Mar. 30, 2011; 135(1-2):96-9. Epub Oct. 16, 2010). Despite some evidence of abnormal global methylation, there is no information on specific loci, patterns of loci, genes, or pathways that are abnormally methylated in rheumatoid arthritis.

Evidence of hypomethylation is not restricted to adaptive immunity in rheumatic disease. Like peripheral blood cells, global genomic hypomethylation was recently reported in RA cultured fibroblast-like synoviocytes (FLS) compared with Osteoarthritis (OA) FLS (Karouzakis E et al. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2009 December; 60(12):3613-22). This observation was associated with relatively low levels of DNMT1 gene expression that were unaffected by in vitro stimulation with IL-1 or TNF. DNMT3a or DNMT3b were not examined, and no studies were performed to determine whether DNMT function was abnormal. Culturing FLS in the presence of 5-azaC for 3 months to block DNA methylation increased expression of several genes implicated in RA. However, it is not certain which genes were hypomethylated and which ones were affected secondary to decreased methylation of other regulatory genes.

DNMT regulation and the methylation status of FLS were examined in view of the association of DNA hypomethylation and an aggressive phenotype in cancer. As shown in this application, it was found that IL-1 significantly decreased DNMT1, DNMT3a, and DNMT3b gene expression within hours. The change in DNMT expression was accompanied by decreased DNMT function in nuclear extracts and global hypomethylation. More striking, an ILLUMINA methylation array study of RA and OA cells showed 100% concordance between DNA methylation patterns and the presence of RA.

The unique patterns of DNA methylation in RA or OA have several implications. The patterns can be used for several applications, including: diagnosis of RA or OA; assessment of disease activity and prognosis of RA or OA; identification of novel therapeutic targets useful for the development of novel therapies for RA or OA; and the development of novel therapies that increase or decrease DNA methylation and alter the pattern, such as though DNMT inhibitors or activators.

DEFINITIONS

As used herein, “methylation” refers to cytosine methylation at positions C5 or N4 of cytosine, the N6 position of adenine or other types of nucleic acid methylation. In particular embodiments, “methylation” refers to cytosine methylation at positions C5 of cytosine, namely, 5-methly cytosine. In vitro amplified DNA is unmethylated because in vitro DNA amplification methods do not retain the methylation pattern of the amplification template. However, “unmethylated DNA” or “methylated DNA” can also refer to amplified DNA whose original template was unmethylated or methylated, respectively.

A “methylation profile” refers to a set of data representing the methylation states of two or more loci within a molecule of DNA from e.g., the genome of an individual or cells or tissues from an individual. The profile can indicate the methylation state of every cytosine base in an individual, can comprise information regarding a subset of the base pairs (e.g., the methylation state of specific restriction enzyme recognition sequence) in a genome, or can comprise information regarding regional methylation density of each locus.

As used herein, “methylation status” refers to the presence, absence and/or quantity of methylation at a particular nucleotide, or nucleotides within a portion of DNA. Determination of the methylation status of a particular DNA sequence (e.g., a locus, a DNA biomarker or DNA region as described herein) can involve determination of the methylation state of every cytosine in the sequence or can involve determination of the methylation state of a subset of the cytosines (such as the methylation state of cytosines in one or more specific restriction enzyme recognition sequences) within the sequence, or can involve determining regional methylation density within the sequence without providing precise information of where in the sequence the methylation occurs. The methylation status can optionally be represented or indicated by a “methylation value.” A methylation value can be generated, for example, by quantifying the amount of intact DNA present following restriction digestion with a methylation dependent restriction enzyme. In this example, if a particular sequence in the DNA is quantified using quantitative PCR, an amount of template DNA approximately equal to a mock treated control indicates the sequence is not highly methylated whereas an amount of template substantially less than occurs in the mock treated sample indicates the presence of methylated DNA at the sequence. Accordingly, a value, i.e., a methylation value, for example from the above described example, represents the methylation status and can thus be used as a quantitative indicator of methylation status. This is of particular use when it is desirable to compare the methylation status of a sequence in a sample to a threshold value.

As used herein, “methylation-dependent restriction enzyme” refers to a restriction enzyme that cleaves or digests DNA at or in proximity to a methylated recognition sequence, but does not cleave DNA at or near the same sequence when the recognition sequence is not methylated. Methylation-dependent restriction enzymes include those that cut at a methylated recognition sequence (e.g., DpnI) and enzymes that cut at a sequence near but not at the recognition sequence (e.g., McrBC). For example, McrBC's recognition sequence is 5′ RmC(N40-3000) RmC 3′ where “R” is a purine and “mC” is a methylated cytosine and “N40-3000” indicates the distance between the two RmC half sites for which a restriction event has been observed. McrBC generally cuts close to one half-site or the other, but cleavage positions are typically distributed over several base pairs, approximately 30 base pairs from the methylated base. McrBC sometimes cuts 3′ of both half sites, sometimes 5′ of both half sites, and sometimes between the two sites. Exemplary methylation-dependent restriction enzymes include, e.g., McrBC (see, e.g., U.S. Pat. No. 5,405,760), McrA, MrrA, BisI, GlaI and DpnI. One of skill in the art will appreciate that any methylation-dependent restriction enzyme, including homologs and orthologs of the restriction enzymes described herein, is also suitable for use in the present embodiments.

As used herein, “methylation-sensitive restriction enzyme” refers to a restriction enzyme that cleaves DNA at or in proximity to an unmethylated recognition sequence but does not cleave at or in proximity to the same sequence when the recognition sequence is methylated. Exemplary methylation-sensitive restriction enzymes are described in, e.g., McClelland et al., Nucleic Acids Res. 22(17):3640-59 (1994) and http://rebase.neb.com. Suitable methylation-sensitive restriction enzymes that do not cleave DNA at or near their recognition sequence when a cytosine within the recognition sequence is methylated at position C5 include, e.g., Aat I I, Aci I, Acd I, Age I, Alu I, Asc I, Ase I, AsiS I, Bbe I, BsaA I, BsaH I, BsiE I, BsiW I, BsrF I, BssH II, BssK I, BstB I, BstN I, BstU I, Cla I, Eae I, Eag I, Fau I, Fse I, Hha I, HinP1 I, HinC II, Hpa II, Hpy99 I, HpyCH4 IV, Kas I, Mbo I, Mlu I, MapA1 I, Msp I, Nae I, Nar I, Not I, Pml I, Pst I, Pvu I, Rsr II, Sac II, Sap I, Sau3A I, Sfl I, Sfo I, SgrA I, Sma I, SnaB I, Tsc I, Xma I, and Zra I. Suitable methylation-sensitive restriction enzymes that do not cleave DNA at or near their recognition sequence when an adenosine within the recognition sequence is methylated at position N6 include, e.g., Mbo I. One of skill in the art will appreciate that any methylation-sensitive restriction enzyme, including homologs and orthologs of the restriction enzymes described herein, is also suitable for use in the present invention. One of skill in the art will further appreciate that a methylation-sensitive restriction enzyme that fails to cut in the presence of methylation of a cytosine at or near its recognition sequence may be insensitive to the presence of methylation of an adenosine at or near its recognition sequence. Likewise, a methylation-sensitive restriction enzyme that fails to cut in the presence of methylation of an adenosine at or near its recognition sequence may be insensitive to the presence of methylation of a cytosine at or near its recognition sequence. For example, Sau3AI is sensitive (i.e., fails to cut) to the presence of a methylated cytosine at or near its recognition sequence, but is insensitive (i.e., cuts) to the presence of a methylated adenosine at or near its recognition sequence. One of skill in the art will also appreciate that some methylation-sensitive restriction enzymes are blocked by methylation of bases on one or both strands of DNA encompassing of their recognition sequence, while other methylation-sensitive restriction enzymes are blocked only by methylation on both strands, but can cut if a recognition site is hemi-methylated.

Evaluating a Diagnosis, Prognosis, or Response to Treatment

Some embodiments provided herein relate to methods for diagnosing, determining a prognosis, or determining or predicting a response to treatment. As used herein, diagnosing can include determining whether a methylation status of 1 or more loci is indicative of a disorder, such as rheumatoid arthritis. As used herein, determining a prognosis can include determining whether methylation status of 1 or more loci is indicative of a likelihood of improvement in symptoms of a disorder, such as rheumatoid arthritis. As used herein, determining or predicting a response to treatment can include determining whether methylation status of 1 or more loci after treatment is more similar to a normal status before treatment or earlier in the treatment regimen. In some embodiments of the methods and compositions provided herein, the 1 or more locus or 1 or more gene is a locus or gene with no known association with RA.

In some such embodiments, the methylation state of at least 1 locus or at least one gene selected from a locus or gene described herein in a sample obtained from a subject is determined. Examples of loci for which the methylation state may be evaluated include the loci listed in TABLE 6, TABLE 7, and TABLE 8. In some embodiments, loci for which the methylation state may be evaluated include SEQ ID NO.s:1-485512. In each sequence provided in SEQ ID NO.s 1-485512, the “C” which is potentially methylated is at position 61. Examples of genes for which the methylation state may be evaluated include the loci listed in TABLE 3. The nucleic acid sequences of the loci listed in TABLE 6, TABLE 7, and TABLE 8 and the genes listed in TABLE 3 are incorporated herein by reference. In some embodiments, additional loci and genes useful for the methods and compositions provided herein can be further identified using the methods described herein. In some embodiments, additional loci and genes useful for the methods and compositions provided herein are identified by conducting methylation analyses in additional samples, thereby providing an increased number of data points which could assist in the identification of further genes or loci having statistically significant differences in their methylation states. The sample can comprise an in vivo sample, an in vitro sample, or an ex vivo sample. It will be understood, that in some embodiments of the compositions or methods provided herein, a sample or cell can be in vivo. In some embodiments of the compositions or methods provided herein, a sample or cell can be ex vivo. Methods to determine the methylation state of at least one locus or at least one gene are well known in the art and examples are provided herein. In some embodiments, the subject is a mammal, such as a human. In some embodiments, the methylation states of at least about 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500 loci or more than 500 loci are determined. Some embodiments also include comparing the methylation state of the at least 1 locus in the sample with the methylation state of the locus in a normal cell, cell from a subject with a known prognosis, or cell from a subject with a known response to treatment. In some embodiments, the methylation states of at least about 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500 genes or more than 500 genes are determined. Some embodiments also include comparing the methylation state of the at least 1 gene in the sample with the methylation state of the gene in a normal cell, cell from a subject with a known prognosis, or cell from a subject with a known response to treatment.

In some embodiments, an increase or decrease in the methylation state of the at least 1 locus compared to the methylation state of the locus in normal cell, cell from a subject with a known prognosis, or cell from a subject with a known response to treatment is indicative of the diagnosis, prognosis, or response to treatment for the subject. In some embodiments, an increase or decrease in the methylation state of a locus selected from the group consisting of the loci listed in TABLE 6 is indicative of the diagnosis, prognosis, or response to treatment for the subject. In some embodiments, an increase or decrease in the methylation state of a locus selected from the group consisting of the loci listed in TABLE 7 is indicative of the diagnosis, prognosis, or response to treatment for the subject. In some embodiments, an increase or decrease in the methylation state of a locus selected from the group consisting of the loci listed in TABLE 8 is indicative of the diagnosis, prognosis, or response to treatment for the subject. In some embodiments, an increase or decrease in the methylation state of the at least 1 gene compared to the methylation state of the gene in a normal cell, cell from a subject with a known prognosis, or tissue from a subject with a known response to treatment is indicative of the diagnosis, prognosis, or response to treatment for the subject. In some embodiments, an increase or decrease in the methylation state of a gene selected from the group consisting of the genes listed in TABLE 3 is indicative of the diagnosis, prognosis, or response to treatment for the subject. In some embodiments, the increase or decrease in methylation occurs in a cell, such as a synoviocyte, such as a fibroblast-like synoviocyte, for example, a rheumatoid arthritis fibroblast-like synoviocyte or an osteoarthritis fibroblast-like synoviocyte. In some embodiments, the cell comprises macrophage. In some embodiments, the cell comprises a peripheral blood cell. As used herein, ‘peripheral blood cell’ can include a cellular component of blood which contains DNA. Examples of peripheral blood cells include white blood cells, including neutrophils, eosinophils, basophils, lymphocytes, B cell, plasma cells, T cells, natural killer cells, monocytes, and dendritic cells. In some embodiments, the cell is mammalian, e.g., human. In some embodiments, the loci and genes which are differentially methylated in fibroblast-like synoviocytes from individuals with rheumatoid arthritis or osteoarthritis and the loci and genes which are differentially methylated in individuals with rheumatoid or osteoarthritis in cell types other than fibroblast-like synoviocytes may partially overlap. However, it is likely that there will be loci and genes which exhibit differential methylation in individuals with rheumatoid arthritis or osteoarthritis in one cell type which are not differentially methylated in other cell types from individuals with rheumatoid arthritis or osteoarthritis. Such differences in differential methylation may be a reflection of the fact that methylation patterns vary among different cell lineages. For example, differentially methylated loci and genes identified in T cells and in B cells types from individuals with rheumatoid arthritis or osteoarthritis can include loci and genes that are different in each cell type. Differentially methylated loci and genes in different cell types from individuals with rheumatoid arthritis or osteoarthritis can be identified using the methods described herein.

Some embodiments include methods of ameliorating rheumatoid arthritis or osteoarthritis in a subject. Some such embodiments include evaluating the methylation status of a plurality of human nucleic acid loci in a nucleic acid sample from a human subject having symptoms of rheumatoid arthritis or osteoarthritis. In some embodiments, the loci comprise at least about 5 loci, at least about 10 loci, at least about 15 loci, at least about 20 loci, at least about 25 loci, at least about 50 loci, and at least about 100 loci. In some embodiments the loci are selected from the group consisting of the loci listed in TABLE 6, TABLE 7, or TABLE 8. In some embodiments, the loci may be selected from SEQ ID NO.s:1-485512. Some embodiments also include administering a treatment for rheumatoid arthritis or osteoarthritis if the loci have a methylation status indicative of rheumatoid arthritis or osteoarthritis.

Some embodiments include a mixture comprising a plurality of human nucleic acid loci from a human subject having symptoms indicative of potential rheumatoid arthritis or osteoarthritis and a reagent capable of providing an indication of the methylation status of said loci. In some embodiments, the loci comprise at least about 5 loci, at least about 10 loci, at least about 15 loci, at least about 20 loci, at least about 25 loci, at least about 50 loci, and at least about 100 loci. In some embodiments the loci are selected from the group consisting of the loci listed in TABLE 6, TABLE 7, or TABLE 8. In some embodiments, the loci are selected from SEQ ID NO.s:1-485512

Methods to Determine Methylation State of a Locus

In some embodiments, the methylation state of more than one DNA region, e.g., gene, locus or portion thereof is determined. In some embodiments, the methylation status of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97 or more than 97 of the DNA regions is determined.

In some embodiments, the methylation state of a DNA region or portion thereof is determined and then normalized (e.g., compared) to the methylation state of a control locus. Typically the control locus will have a known, relatively constant, methylation status. For example, the control sequence can be previously determined to have no, some or a high amount of methylation, thereby providing a relative constant value to control for error in detection methods, etc., unrelated to the presence or absence of a disorder. In some embodiments, the control locus is endogenous, i.e., is part of the genome of the individual sampled. For example, in mammalian cells, the testes-specific histone 2B gene (hTH2B in human) gene is known to be methylated in all somatic tissues except testes. Alternatively, the control locus can be an exogenous locus, i.e., a DNA sequence spiked into the sample in a known quantity and having a known methylation status.

A DNA region comprises a nucleic acid including one or more methylation sites of interest (e.g., a cytosine, a “microarray feature,” or an amplicon amplified from select primers) and flanking nucleic acid sequences (i.e., “wingspan”) of up to 4 kilobases (kb) in either or both of the 3′ or 5′ direction from the amplicon. This range corresponds to the lengths of DNA fragments obtained by randomly fragmenting the DNA before screening for differential methylation between DNA in two or more samples (e.g., carrying out methods used to initially identify differentially methylated loci). In some embodiments, the wingspan of the one or more DNA regions is about 0.5 kb, 0.75 kb, 1.0 kb, 1.5 kb, 2.0 kb, 2.5 kb, 3.0 kb, 3.5 kb or 4.0 kb in both 3′ and 5′ directions relative to the sequence represented by the microarray feature. The DNA region of interest can comprise and/or be immediately adjacent to a locus selected from the group consisting of the loci listed in TABLE 6, TABLE 7, or TABLE 8, or a gene selected from a gene listed in TABLE 3. In some embodiments, the locus may be selected from SEQ ID NO.s:1-485512. The nucleic acid sequences of the loci listed in TABLE 6, TABLE 7, and TABLE 8 are available, for example, in the Illumina CpG database, and included in SEQ ID NO.s:1-485512.

The methylation sites in a DNA region can reside in non-coding transcriptional control sequences (e.g., promoters, enhancers, etc.) or in coding sequences, including introns and exons of the loci listed in TABLE 6, TABLE 7, or TABLE 8, and genes listed in TABLE 3. In some embodiments, the methods comprise detecting the methylation status in the promoter regions (e.g., comprising the nucleic acid sequence that is about 1.0 kb, 1.5 kb, 2.0 kb, 2.5 kb, 3.0 kb, 3.5 kb or 4.0 kb 5′ from the transcriptional start site through to the translational start site) of one or more of the locus identified in TABLE 6, TABLE 7, TABLE 8, or TABLE 3. In some embodiments, the locus may be selected from SEQ ID NO.s:1-485512.

Any method for detecting DNA methylation can be used in the methods provided herein. In some embodiments, an array can be used to determine the methylation state of at least one locus, such as the ILLUMINA HumanMethylation 450 BeadChip. DNA is treated with bisulfite to convert unmethylated cytosines to uracil, methylated cytosines are protected and remain cytosine. After the conversion step, a determination step is performed to identify whether a base at a particular locus was converted. Methylation status of the interrogated site is calculated as the ratio of the signal from a methylated probe relative to the sum of both methylated and unmethlylated probes. This value, known as β, ranges continuously from 0 (unmethlylated) to 1 (fully methylated). Arrays, such as the ILLUMINA HumanMethylation 450 BeadChip, include genes and CpG islands and other sequences.

In some embodiments, methods for detecting methylation include randomly shearing or randomly fragmenting the genomic DNA, cutting the DNA with a methylation-dependent or methylation-sensitive restriction enzyme and subsequently selectively identifying and/or analyzing the cut or uncut DNA. Selective identification can include, for example, separating cut and uncut DNA (e.g., by size) and quantifying a sequence of interest that was cut or, alternatively, that was not cut. See, e.g., U.S. Pat. No. 7,186,512. Alternatively, the method can encompass amplifying intact DNA after restriction enzyme digestion, thereby only amplifying DNA that was not cleaved by the restriction enzyme in the area amplified. See, e.g., U.S. patent application Ser. Nos. 10/971,986; 11/071,013; and 10/971,339. In some embodiments, amplification can be performed using primers that are gene specific. Alternatively, adaptors can be added to the ends of the randomly fragmented DNA, the DNA can be digested with a methylation-dependent or methylation-sensitive restriction enzyme, intact DNA can be amplified using primers that hybridize to the adaptor sequences. In this case, a second step can be performed to determine the presence, absence or quantity of a particular gene in an amplified pool of DNA. In some embodiments, the DNA is amplified using real-time, quantitative PCR.

In some embodiments, the methods comprise quantifying the average methylation density in a target sequence within a population of genomic DNA. In some embodiments, the method comprises contacting genomic DNA with a methylation-dependent restriction enzyme or methylation-sensitive restriction enzyme under conditions that allow for at least some copies of potential restriction enzyme cleavage sites in the locus to remain uncleaved; quantifying intact copies of the locus; and comparing the quantity of amplified product to a control value representing the quantity of methylation of control DNA, thereby quantifying the average methylation density in the locus compared to the methylation density of the control DNA.

The quantity of methylation of a locus of DNA can be determined by providing a sample of genomic DNA comprising the locus, cleaving the DNA with a restriction enzyme that is either methylation-sensitive or methylation-dependent, and then quantifying the amount of intact DNA or quantifying the amount of cut DNA at the DNA locus of interest. The amount of intact or cut DNA will depend on the initial amount of genomic DNA containing the locus, the amount of methylation in the locus, and the number (i.e., the fraction) of nucleotides in the locus that are methylated in the genomic DNA. The amount of methylation in a DNA locus can be determined by comparing the quantity of intact DNA or cut DNA to a control value representing the quantity of intact DNA or cut DNA in a similarly-treated DNA sample. The control value can represent a known or predicted number of methylated nucleotides. Alternatively, the control value can represent the quantity of intact or cut DNA from the same locus in another (e.g., normal, non-diseased) cell or a second locus.

By using at least one methylation-sensitive or methylation-dependent restriction enzyme under conditions that allow for at least some copies of potential restriction enzyme cleavage sites in the locus to remain uncleaved and subsequently quantifying the remaining intact copies and comparing the quantity to a control, average methylation density of a locus can be determined. As used herein, ‘methylation density’ can refer to the number of methylated C-residues within a region. If the methylation-sensitive restriction enzyme is contacted to copies of a DNA locus under conditions that allow for at least some copies of potential restriction enzyme cleavage sites in the locus to remain uncleaved, then the remaining intact DNA will be directly proportional to the methylation density, and thus may be compared to a control to determine the relative methylation density of the locus in the sample. Similarly, if a methylation-dependent restriction enzyme is contacted to copies of a DNA locus under conditions that allow for at least some copies of potential restriction enzyme cleavage sites in the locus to remain uncleaved, then the remaining intact DNA will be inversely proportional to the methylation density, and thus may be compared to a control to determine the relative methylation density of the locus in the sample. Such assays are disclosed in, e.g., U.S. patent application Ser. No. 10/971,986.

Quantitative amplification methods (e.g., quantitative PCR or quantitative linear amplification) can be used to quantify the amount of intact DNA within a locus flanked by amplification primers following restriction digestion. Methods of quantitative amplification are disclosed in, e.g., U.S. Pat. Nos. 6,180,349; 6,033,854; and 5,972,602, as well as in, e.g., Gibson et al., Genome Research 6:995-1001 (1996); DeGraves, et al., Biotechniques 34(1):106-10, 112-5 (2003); Deiman B, et al., Mol. Biotechnol. 20(2):163-79 (2002). Amplifications may be monitored in “real time.”

Additional methods for detecting DNA methylation can involve genomic sequencing before and after treatment of the DNA with bisulfite. See, e.g., Frommer et al., Proc. Natl. Acad. Sci. USA 89:1827-1831 (1992). When sodium bisulfite is contacted to DNA, unmethylated cytosine is converted to uracil, while methylated cytosine is not modified.

In some embodiments, restriction enzyme digestion of PCR products amplified from bisulfite-converted DNA is used to detect DNA methylation. See, e.g., Sadri & Hornsby, Nucl. Acids Res. 24:5058-5059 (1996); Xiong & Laird, Nucleic Acids Res. 25:2532-2534 (1997).

In some embodiments, a MethyLight assay is used alone or in combination with other methods to detect DNA methylation (see, Eads et al., Cancer Res. 59:2302-2306 (1999)). Briefly, in the MethyLight process genomic DNA is converted in a sodium bisulfite reaction (the bisulfite process converts unmethylated cytosine residues to uracil). Amplification of a DNA sequence of interest is then performed using PCR primers that hybridize to CpG dinucleotides. By using primers that hybridize only to sequences resulting from bisulfite conversion of unmethylated DNA, (or alternatively to methylated sequences that are not converted) amplification can indicate methylation status of sequences where the primers hybridize. Similarly, the amplification product can be detected with a probe that specifically binds to a sequence resulting from bisulfite treatment of a unmethylated (or methylated) DNA. If desired, both primers and probes can be used to detect methylation status. Thus, kits for use with MethyLight can include sodium bisulfite as well as primers or detectably-labeled probes (including but not limited to Taqman or molecular beacon probes) that distinguish between methylated and unmethylated DNA that have been treated with bisulfite. Other kit components can include, e.g., reagents necessary for amplification of DNA including but not limited to, PCR buffers, deoxynucleotides; and a thermostable polymerase.

In some embodiments, a Ms-SNuPE (Methylation-sensitive Single Nucleotide Primer Extension) reaction is used alone or in combination with other methods to detect DNA methylation (see, Gonzalgo & Jones, Nucleic Acids Res. 25:2529-2531 (1997)). The Ms-SNuPE technique is a quantitative method for assessing methylation differences at specific CpG sites based on bisulfite treatment of DNA, followed by single-nucleotide primer extension (Gonzalgo & Jones, supra). Briefly, genomic DNA is reacted with sodium bisulfite to convert unmethylated cytosine to uracil while leaving 5-methylcytosine unchanged. Amplification of the desired target sequence is then performed using PCR primers specific for bisulfite-converted DNA, and the resulting product is isolated and used as a template for methylation analysis at the CpG site(s) of interest.

Typical reagents (e.g., as might be found in a typical Ms-SNuPE-based kit) for Ms-SNuPE analysis can include, but are not limited to: PCR primers for specific gene (or methylation-altered DNA sequence or CpG island); optimized PCR buffers and deoxynucleotides; gel extraction kit; positive control primers; Ms-SNuPE primers for a specific gene; reaction buffer (for the Ms-SNuPE reaction); and detectably-labeled nucleotides. Additionally, bisulfite conversion reagents may include: DNA denaturation buffer; sulfonation buffer; DNA recovery regents or kit (e.g., precipitation, ultrafiltration, affinity column); desulfonation buffer; and DNA recovery components.

In some embodiments, a methylation-specific PCR (“MSP”) reaction is used alone or in combination with other methods to detect DNA methylation. An MSP assay entails initial modification of DNA by sodium bisulfite, converting all unmethylated, but not methylated, cytosines to uracil, and subsequent amplification with primers specific for methylated versus unmethylated DNA. See, Herman et al., Proc. Natl. Acad. Sci. USA 93:9821-9826, (1996); U.S. Pat. No. 5,786,146.

Additional methylation detection methods include, but are not limited to, methylated CpG island amplification (see, Toyota et al., Cancer Res. 59:2307-12 (1999)) and those described in, e.g., U.S. Patent Publication 2005/0069879; Rein, et al. Nucleic Acids Res. 26 (10): 2255-64 (1998); Olek, et al. Nat. Genet. 17(3): 275-6 (1997); and PCT Publication No. WO 00/70090.

Some embodiments provided herein include methods of determining the methylation status of a plurality of human nucleic acid loci. Some such embodiments include contacting a nucleic acid sample from a human subject with a reagent capable of providing an indication of the methylation status of said loci. In some embodiments, the loci comprise at least about 5 loci, at least about 10 loci, at least about 15 loci, at least about 20 loci, at least about 25 loci, at least about 50 loci, and at least about 100 loci. In some embodiments the loci are selected from the group consisting of the loci listed in TABLE 6, TABLE 7, or TABLE 8. In some embodiments, the reagent is a restriction enzyme. In some embodiments, the reagent is a primer. In some embodiments, the reagent is a probe. In some embodiments, the reagent comprises sodium bisulfite.

Identifying Therapeutic Agents

Some embodiments provided herein relate to methods for identifying therapeutic agents. Some such embodiments for identifying therapeutic agents which may be used to treat rheumatoid arthritis or osteoarthritis, can include contacting a cell with a test agent; and determining the methylation state of at least 1 locus selected from the loci listed in TABLE 6, TABLE 7, or TABLE 8 or at least one gene listed in Table 3 in the contacted cell. In some embodiments, the at least one locus may be selected from SEQ ID NO.s:1-485512. Some methods also include comparing the methylation state of the at least 1 locus, or at least 1 gene in the contacted cell with the methylation state of the locus or the gene in the cell not contacted with the test agent, and selecting a test agent that increases or decreases the methylation state of the at least 1 locus or the at least 1 gene in the cell contacted with the test agent compared to the methylation state of the locus or the gene in a cell not contacted with the test agent. For example, if a locus, a gene group of loci or group of genes are hypermethylated in individuals with RA, agents which reduce the level of methylation at the locus, the gene, group of loci or group of genes may be useful as therapeutic agents. Likewise, if a locus, a gene, group of loci or group of genes are hypomethylated in individuals with RA, agents which increase the level of methylation at the locus, the gene group of loci or group of genes may be useful as therapeutic agents. Likewise, agents which produce a methylation profile in cells contacted with the agent having a greater similarity to the methylation profile of individuals who do not suffer from RA relative to the methylation profile in cells which have not been contacted with the agent may be useful as therapeutic agents. Examples of test agents and potential therapeutic agents include small molecules (including but not limited to organic chemical compounds which have been obtained from natural sources or synthesized), nucleic acids (including but not limited to antisense nucleic acids, ribozymes, or siRNAs), peptides and proteins (including but not limited to cytokines TNF-α, and DMNTs).

In some embodiments, at least 1 locus is selected from the group consisting of the loci listed in TABLE 6. In some embodiments, at least 1 locus is selected from the group consisting of the loci listed in TABLE 7. In some embodiments, the at least one locus may be selected from SEQ ID NO.s:1-485512. In some embodiments, at least 1 gene is selected from the group consisting of the gene listed in TABLE 3.

In some embodiments, the methylation states of at least about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, or TABLE 8 are determined. In some embodiments, the methylation states of at least about 5, 10, 20, 30, 40, 50, 60, 70, 80, or 100 loci selected from the group consisting of the loci of SEQ ID NO.s:1-485512. In some embodiments, the methylation states of at least about 1, 5, 10, 20, 30, 40, 50 genes selected from the group consisting of the genes listed in TABLE 3 are determined

In some embodiments, the cell comprises a synoviocyte, such as a fibroblast-like synoviocyte, for example, a rheumatoid arthritis fibroblast-like synoviocyte or an osteoarthritis fibroblast-like synoviocyte. In some embodiments, the cell comprises a macrophage. In some embodiments, the cell comprises a peripheral blood cell. In some embodiments, the peripheral blood cell is selected from the group consisting of white blood cell, including neutrophil, eosinophil, basophil, lymphocyte, B cell, plasma cell, T cell, natural killer cell, monocyte, and dendritic cell. In some embodiments, the cell is mammalian, e.g., human.

More embodiments of methods for identifying therapeutic reagents include identifying agents that modulate methylation of genes encoding proteins that act in the same pathway as other proteins encoded by genes that are differentially methylated in rheumatoid arthritis or osteoarthritis or agents which modulate the activity of proteins in the same pathway as proteins encoded by genes which are differentially methylated in rheumatoid arthritis or osteoarthritis. Some methods for identifying a therapeutic agent for treating rheumatoid arthritis or osteoarthritis include contacting a cell with a test agent, and determining the methylation state of at least 1 gene selected from a gene encoding a protein that acts in a pathway that includes a protein encoded by a gene that is differentially methylated in a rheumatoid arthritis cell or osteoarthritis cell compared to a normal cell. Some methods also include comparing the methylation state of the at least 1 gene in the contacted cell with the methylation state of the gene in a cell which was not contacted with the test agent, selecting a test agent that increases or decreases the extent of methylation of the at least 1 gene in the cell contacted with the test agent compared to the extent of methylation of the at least 1 gene in a cell which was not contacted with the test agent such that the extent of methylation of the at least 1 gene in the cell contacted with the test agent is a methylation state associated with the absence of rheumatoid arthritis or osteoarthritis or with a reduction in the symptoms associated with rheumatoid arthritis or osteoarthrities. In some embodiments, the pathway is selected from focal adhesion, glycosphingolipid biosynthesis—lacto and neolacto series, arrhythmogenic right ventricular cardiomyopathy (ARVC), ECM-receptor interaction, amoebiasis, leukocyte transendothelial migration, protein digestion and absorption, cell adhesion molecules (CAMs), nitrogen metabolism, ErbB signaling pathway, African trypanosomiasis, primary bile acid biosynthesis, Fc epsilon RI signaling pathway, mTOR signaling pathway, and adipocytokine signaling pathway.

Kits

Some embodiments provided herein relate to kits. Some such kits can be useful for diagnosing, determining a prognosis, or determining a response to treatment of a subject with a disorder, such as rheumatoid arthritis, comprising: a reagent for determining the methylation state of at least one locus selected from the group consisting of the loci listed in TABLE 6, TABLE 7, or TABLE 8. In some embodiments, the at least one locus may be selected from SEQ ID NO.s:1-485512. In some embodiments, the kit also includes at least one polynucleotide primer comprising a sequence hybridizing to at least a portion of the at least one locus selected from the group consisting of the loci listed in TABLE 6, TABLE 7, or TABLE 8. In some embodiments, the locus may be selected from SEQ ID NO.s:1-485512. In some embodiments, the kit can include one or more of methylation-dependent restriction enzymes, methylation-sensitive restriction enzymes, amplification (e.g., PCR) reagents, probes and/or primers. In some embodiments a reagent can determine the methylation states of at least about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more than 100 loci selected from the group consisting of the loci listed in TABLE 6, TABLE 7, or TABLE 8. In some embodiments, the at least about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more than 100 loci may be selected from SEQ ID NO.s:1-485512.

Some embodiments include kits for diagnosing, determining a prognosis, or determining or predicting a response to treatment of a subject with rheumatoid arthritis or osteoarthritis, comprising a reagent for determining the methylation state of at least one gene selected from the group consisting of the genes listed in TABLE 3. Some kits also include at least one polynucleotide primer comprising a sequence hybridizing to at least a portion of the at least one gene selected from the group consisting of the genes listed in TABLE 3. In some embodiments, the reagent comprises a restriction enzyme. In some embodiments a reagent can determine the methylation states of at least about 1, 5, 10, 20, 30, 40, 50, or more genes selected from the group consisting of the genes listed in TABLE 3.

Some embodiments include a nucleic acid array consisting essentially of nucleic acids useful for diagnosing rheumatoid arthritis or osteoarthritis, determining a prognosis of rheumatoid arthritis or osteoarthritis, or determining or predicting a response to treatment of a subject being evaluated for or suffering from rheumatoid arthritis or osteoarthritis. In some such embodiments, the nucleic acids comprise at least about 5 loci, at least about 10 loci, at least about 15 loci, at least about 20 loci, at least about 25 loci, at least about 50 loci, and at least about 100 loci. In some embodiments the loci are selected from the group consisting of the loci listed in TABLE 6, TABLE 7, or TABLE 8. In some embodiments, the loci may be selected from SEQ ID NO.s:1-485512.

Computer-Based Methods

The calculations for the methods described herein can involve computer-based calculations and tools. For example, a methylation value for a DNA region or portion thereof can be compared by a computer to a threshold value, as described herein. The tools are advantageously provided in the form of computer programs that are executable by a general purpose computer system (referred to herein as a “host computer”) of conventional design. The host computer may be configured with many different hardware components and can be made in many dimensions and styles (e.g., desktop PC, laptop, tablet PC, handheld computer, server, workstation, mainframe). Standard components, such as monitors, keyboards, disk drives, CD and/or DVD drives, and the like, may be included. Where the host computer is attached to a network, the connections may be provided via any suitable transport media (e.g., wired, optical, and/or wireless media) and any suitable communication protocol (e.g., TCP/IP); the host computer may include suitable networking hardware (e.g., modem, Ethernet card, WiFi card). The host computer may implement any of a variety of operating systems, including UNIX, Linux, Microsoft Windows, MacOS, or any other operating system.

Computer code for implementing aspects of the present invention may be written in a variety of languages, including PERL, C, C++, Java, JavaScript, VBScript, AWK, or any other scripting or programming language that can be executed on the host computer or that can be compiled to execute on the host computer. Code may also be written or distributed in low level languages such as assembler languages or machine languages.

The host computer system advantageously provides an interface via which the user controls operation of the tools. In the examples described herein, software tools are implemented as scripts (e.g., using PERL), execution of which can be initiated by a user from a standard command line interface of an operating system such as Linux or UNIX. Those skilled in the art will appreciate that commands can be adapted to the operating system as appropriate. In other embodiments, a graphical user interface may be provided, allowing the user to control operations using a pointing device. Thus, the present invention is not limited to any particular user interface.

Scripts or programs incorporating various features of the present invention may be encoded on various computer readable media for storage and/or transmission. Examples of suitable media include magnetic disk or tape, optical storage media such as compact disk (CD) or DVD (digital versatile disk), flash memory, and carrier signals adapted for transmission via wired, optical, and/or wireless networks conforming to a variety of protocols, including the Internet.

Some embodiments include methods for diagnosing rheumatoid arthritis or osteoarthritis, determining a rheumatoid arthritis or osteoarthritis prognosis, or determining or predicting a response to treatment for rheumatoid arthritis or osteoarthritis in a subject comprising accessing first data representing nucleic acid loci which are differentially methylated in individuals with rheumatoid arthritis, osteoarthritis a rheumatoid arthritis or osteoarthritis prognosis, or a response to treatment for rheumatoid arthritis or osteoarthritis wherein said data is stored on a non-transitory computer readable medium. Some embodiments also include instructing a computer to compare said first data to second data representing the methylation status of said nucleic acid loci in a sample taken from said subject, wherein said data representing the methylation status of said nucleic acid loci in a sample taken from said subject is stored on a non-transitory computer readable medium. Some embodiments also include diagnosing rheumatoid arthritis or osteoarthritis, determining a rheumatoid arthritis or osteoarthritis prognosis, or determining or predicting a response to treatment for rheumatoid arthritis or osteoarthritis in said subject if said first data representing the methylation status of said nucleic acid loci in a sample taken from said subject are significantly similar to said second data representing nucleic acid loci which are differentially methylated in individuals with rheumatoid arthritis, osteoarthritis a rheumatoid arthritis or osteoarthritis prognosis, or a response to treatment for rheumatoid arthritis or osteoarthritis.

While the present invention has been described in some detail for purposes of clarity and understanding, one skilled in the art will appreciate that various changes in form and detail can be made without departing from the true scope of the invention.

EXAMPLES
Example 1
Methylation of Loci in RA and OA Patients
Methods: Fibroblast-Like Synoviocytes

FLS were isolated from synovial tissues obtained from RA and OA patients at the time of joint replacement as described previously. The diagnosis of RA conformed to the American College of Rheumatology 1987 revised criteria. The protocol was approved by the UCSD Human Subjects Research Protection Program. Synovial tissues were minced and incubated with 0.5 mg/ml collagenase VIII (Sigma) in serum-free RPMI (Mediatech, VA) for 1.5 h at 37° C., filtered through a 0.22 μm cell strainer, extensively washed, and cultured in DMEM supplemented with 10% FCS (endotoxin content<0.006 ng/ml; Gemini Biosciences, CA), penicillin, streptomycin, gentamicin and L-glutamine in a humidified 5% CO₂incubator. After overnight culture, nonadherent cells were removed, and adherent cells were trypsinized, split at a 1:3 ratio, and cultured. Synoviocytes were used from passage 4 through 9, when FLS were a homogeneous population with <1% CD11b, <1% phagocytic, and <1% FcR II positive cells.

Patient Phenotype

Synovial tissues were obtained at the time of clinically indicated total knee or hip joint replacement surgery except for one patient with RA who had wrist surgery. The mean ages of RA and OA patients were 53±9 and 68±16, respectively. Additional information on four patients (2 RA and 2 OA) was limited because the samples were de-identified. The erythrocyte sedimentation rates for the remaining RA and OA patients were 38±15 and 19±10, respectively. Of the 4 RA patients with clinical information, 3 were seropositive for serum rheumatoid factor or anti-CCP antibody and all were treated with low dose prednisone, 2 with methotrexate, 2 with a TNF blocker, and 1 with leflunomide. OA was mainly treated with acetaminophin and narcotics for pain.

Isolation of Genomic DNA and qPCR Analysis

RA and OA FLS were grown to 80% confluence and harvested. Genomic DNA of 10⁶FLS was isolated using the MagMAX™ DNA Multi-Sample Kit (Applied Biosystems). DNA quality and quantity was assessed with a NanoDrop ND-2000 spectrometer (NanoDrop Technologies, Wilmington, Del., USA). mRNA from cultured FLS was isolated using RNA-STAT (Tel-Stat, TX) and cDNA was prepared, according to manufacturer's instructions using GeneAmp 2400 (Applied Biosystems). Quantitative real-time PCR was performed using Assays On Demand (Applied Biosystems) to determine relative mRNA levels using the GeneAmp 5700 Sequence Detection System (Applied Biosystems) as described previously. Standard curves for human MMP1 and GAPDH were generated. Sample Ct values were used to calculate the number of cell equivalents in the test samples. The data were then normalized to GAPDH expression to obtain relative cell equivalents.

Infinium HumanMethylation450 Chip Analysis

Genomic DNA was isolated from female RA and OA FLS as described. The Infinium HumanMethylation450 chip was processed as described by the manufacturer (Illumina, San Diego, Calif.). This chip covers 96% of RefSeq genes and provides comprehensive gene region coverage, targeting multiple sites with promoter, 5□ UTR, 1st exon, gene body and 3□ UTR. Initial analysis was performed with the Genome Studio methylation module, and then further analysed as described herein. The methylation level of a loci is measured as:

β=M/(U+M+100)

M is the fluorescence level of the methylation probe and U is the methylation level of the unmethylated probe. A constant value of 100 is added to prevent division by a small number (or 0) when background subtraction was used. The β values varied from 0 (completely unmethylated) to 1 (completely methylated). To measure the difference in methylation at a loci between OA and RA the average β levels were compared.

Method for Determining Enrichment of Multiple Methylated Loci

To avoid taking a single P-value cut-off when identifying genes that are enriched with differentially methylated (differentially methylated) loci, a variable cut-off scheme was used. Loci were ranked by their differentially methylated P-values. Then a P-value cut-off was taken. Those loci with P-value beneath the cut-off were taken to be differentially methylated and the rest were taken as not being differentially methylated. While doing this all P-value cut-offs beneath 0.05 were tried. Then for each gene, with loci beneath the P-value cut-off, the level which its loci were enriched beneath the cut-off was calculated as its enrichment factor (EF).

EF=(number of loci from gene A beneath cut-off/total loci from gene A)/(total number of loci beneath cut-off/total number of loci)

If EF is greater than 1 then it means the genes loci are enriched with differentially methylated loci. For those genes with an EF greater than 1, a P-value for the level of enrichment was calculated using the hypergeometric distribution. The resulting P-values were corrected with the Benjamini-Hochberg correction. Genes with enrichment P-values beneath <0.05 were recorded. If a gene was found to be enriched at multiple loci differentially methylated levels then only the level with the lower enrichment P-value was reported.

Pathway and Gene Ontology Analyses

Pathway enrichment was carried out using the KEGG human pathways and modules (www.genome.jp/kegg/download). The enrichment analysis of 1859 loci was performed by mapping pathway to loci via the loci gene annotations, the EF of loci being enriched in KEGG pathway as calculated. If EF was greater than 1 then P-value for the level of enrichment was calculated using the hypergeometric distribution. The resulting P-values were corrected with the Benjamini-Hochberg correction. As the KEGG pathways represent groups of related bimolecular pathways a P-value cut-off of <0.1 was used as it would allow enrichment within individual bimolecular pathways to be identified. A P-value cut-off of <0.1 has been used previously during KEGG pathway analysis (Xu et al. 2010-Revealing parasite influence in metabolic pathways in Apicomplexa infected patients, BMC Bioinformatics 2010, 11(Suppl 11):S13; Shen et al. 2006—Sepsis Plasma Protein Profiling with Immunodepletion, Three-Dimensional Liquid Chromatography Tandem Mass Spectrometry, and Spectrum Counting, J. Proteome Res., 2006, 5 (11), pp 3154-3160, each incorporated by reference in their entireties). Gene ontology (GO) analysis was carried using human GO term associations (www.geneontology.org). GO term enrichment analysis was carried out using model-based gene set analysis which uses probabilistic inference to identify the active GO terms (Bauer, et al. 2010 GOing Bayesian: model-based gene set analysis of genome-scale data. Nucleic Acids Res. 2010; 38:3523-32, incorporated by reference in its entirety). This approach naturally deals with overlapping GO categories and avoids the need for multiple testing correction. Marginal probability values>0.50 were considered significantly enriched.

Initial Probe and Data Filtering

The DNA methylome in RA and control (OA) FLS was evaluated. The Infinium HumanMethylation450 chip (Illumina, Inc.) was used to determine the methylation status of 485,512 loci from FLS isolated from 11 female patients at the time of total joint replacement surgery (6 RA; 5 OA). Loci were removed from subsequent analysis if any of the probes for a locus could not be disguised from background with a P-value<0.01 or if enough beads present upon the chip for accurate measurement of their methylation level. After filtering, 476,331 loci were available for further analysis.

Global Methylation Status

To assess global methylation status of RA and OA FLS, the methylation scores over all filtered loci within a sample were summed. The difference between the two samples was assessed using Student's t-test. Initial analysis included all loci and was then repeated for only loci located in promoters. There were no significant differences between RA and OA (P-values 0.528 and 0.627, respectively). Therefore, globally hypo- or hypermethylation is not associated with RA when compared to OA. These results were confirmed using an antibody-based method to determine methylcytosine levels (Active Motif, Inc., Carlsbad, Calif.) where global methylation were similar for RA and OA (RA=0.85±0.32; OA=1.00±0.24; n=10 RA and 9 OA lines; P>0.05).

Analysis of Differentially Methylated Individual Loci

Although global methylation are not different for RA and OA, there were differentially methylated (differentially methylated) loci that cluster to the two diseases. To identify the autosomal loci that are differentially methylated between OA and RA two filters were used: (i) an average difference in methylation level was greater than 0.1; and (ii) a P-value<0.05 that calculated using the Student's t-test and corrected for multiple testing with the Benjamini-Hochberg adjustment. 1,859 loci in 1206 different genes were identified as significantly differentially methylated in RA FLS. TABLE 1 shows example numbers of hypermethylated and hypomethylated sites.

TABLE 1

No. of loci
No. of loci

hypomethylated
hypermethylated

in RA
in RA

differentially methylated loci*
732
1127

differentially methylated genes**
63
144

differentially methylated KEGG
10
6

pathways

differentially methylated GO
138
242

terms

*differentially methylated = Differentially methylated; Difference between OA and RA > 0.1, with P < 0 after Benjamini-Hochberg adjustment.

**6 additional genes had both hypo- and hypermethylated loci (ADAMTS2, C7orf50, DIP2C, FRMD SH3PXD2A)

Examples of genes identified with statistically significant differences between RA and OA at an individual locus using the ILLUMINA dataset are shown in TABLE 2. A mean value of OA methylation minus RA methylation; A P-value cut-off of <0.05 was used for determining significance. Where the RA minus OA value was positive the locus in RA was hypermethylated; where the RA minus OA value was negative, the locus in RA was hypomethylated.

TABLE 2

RA minus OA
Gene
Description

Hyper-
−0.34417
PHLPP1
PH domain and leucine rich repeat protein phosphatase 1

methylated*
−0.34108
RXRA
retinoid X receptor, alpha

−0.30861
CYFIP1
cytoplasmic FMR1 interacting protein 1

−0.30363
ADAMTS2
ADAM metallopeptidase with thrombospondin type 1 motif, 2

−0.2964
CD55
CD55 molecule, decay accelerating factor for complement

−0.27459
CABLES1
Cdk5 and Abl enzyme substrate 1

−0.26569
HAS1
hyaluronan synthase 1

−0.25362
ITGB8
integrin, beta 8

−0.25333
HBEGF
heparin-binding EGF-like growth factor

−0.23299
PTPN14
protein tyrosine phosphatase, non-receptor type 14

−0.23228
COL4A2
collagen, type IV, alpha 2

−0.23122
COL4A1
collagen, type IV, alpha 1

−0.21314
TGFBR2
transforming growth factor, beta receptor II (70/80 kDa)

−0.20915
EGF
epidermal growth factor

−0.20692
ITGBL1
integrin, beta-like 1 (with EGF-like repeat domains)

−0.20006
TIMP2
TIMP metallopeptidase inhibitor 2

−0.19768
MAP3K1
mitogen-activated protein kinase kinase kinase 1

−0.19005
FOXO1
forkhead box O1

Hypo-
0.365
CHI3L1
Chitinase 3-like 1 (cartilage glycoprotein-39)

methylated
0.337
WISP3;
WNT1 inducible signaling pathway protein 3

WISP3

0.333
STK24
serine/threonine kinase 24

0.329
MMP20
matrix metallopeptidase 20

0.322
EGFLAM
EGF-like, fibronectin type III and laminin G domain

0.318
PTGIS
prostaglandin I2 (prostacyclin) synthase

0.301
DCBLD1
discoidin, CUB and LCCL domain containing 1

0.299
MAP3K5
mitogen-activated protein kinase kinase kinase 5 (ASK1)

0.297
MGMT
O-6-methylguaninE−DNA methyltransferase

0.282
CDK14
Cyclin-dependent kinase 14

0.272
STAT3
signal transducer and activator of transcription 3

0.270
ADAM32
ADAM metallopeptidase domain 32

0.264
RASGRF2
Ras protein-specific guanine nucleotidE−releasing factor 2

0.253
CASP1
caspase 1, apoptosis-related cysteine peptidase

0.225
P2RX6
purinergic receptor P2X, ligand-gated ion channel, 6

0.195
TRAF2
TNF receptor-associated factor 2

0.185
MEFV
Mediterranean fever

CpG methylation was significantly different in a number of genes implicated in RA. Several genes implicated in inflamation and immune responses are differentially methylated in RA.

A list of 1,859 loci is shown in TABLE 6 and TABLE 7. TABLE 6 and TABLE 7 list loci which are differentially methylated in RA compared to OA; a positive OA-RA value represents a loci which is hypomethylated in RA FLS (TABLE 6), a negative OA-RA value represents a loci which is hypermethylated in RA FLS (TABLE 7).

Permutation analysis was carried out to assess the significance of loci identified as differentially methylated. The 11 samples were randomly assigned to OA and RA while maintaining the same number of OA and RA labels, i.e., 5 OA and 6 RA. The permutation analysis was repeated 1,000 times. The average number of significant loci during the permutation analysis was 4.9, compared to 1,859 for the correct disease identification. The permutation analysis strongly supports these loci as truly differentially methylated and not as a result of random chance.

To assess the ability of the 1,859 loci to distinguish OA from RA, the methylation patterns of the loci across the 11 samples were hierarchically clustered (FIG. 2). The clustering of the samples distinguishes OA from RA, which clearly segregate according to disease type. The clustering of the loci also shows that groups of loci have similar patterns of differentially methylated across the samples.

Analysis of Genes with Multiple Differentially Methylated Loci

To examine genes that were significantly differentially methylated between OA and RA, genes that were enriched with multiple differentially methylated loci were identified (see Methods). This analysis was carried using all 1,859 differentially methylated loci identified in differentially methylated loci section. The data demonstrated that many genes have multiple CpGs that are hyper- or hypo-methylated. For example, COL1A1 has 41 loci, and 4 are hypomethylated in RA (P<10⁻⁶) giving a “relative enrichment” of 79-fold compared to OA. Relative enrichment for MEFV (pyrin) hypomethylation is nearly 200-fold. Of interest, 4 of 16 loci in the TNF promoter are hypermethylated in RA (relative enrichment-451; P<10⁻⁹), suggesting that TNF regulation might be under the control of DNMTs in some patients. 207 genes were either enriched for multiple hyper- or hypomethylated loci (TABLE 1). Representative examples of hypomethylated- (hypo-) and hypermethylated- (hyper-) differentially methylated genes are shown in TABLE 3.

TABLE 3

No. of

differentially
Total

methylated
loci

Enrich-

Status

loci beneath
on
P-value for
ment

in RA
Gene
cut-off
array
enrichment
factor

hypo
LOC146880
9
32
9.96E−18
245.34

hypo
SH3D20
6
15
5.58E−14
487.22

hypo
TACC2
7
70
4.60E−11
87.23

hypo
KCNJ9
4
15
1.95E−08
251.27

hypo
FUT4
4
20
4.90E−08
200.26

hypo
ARHGAP27
4
25
2.45E−07
130.45

hypo
OLFML3
3
9
2.97E−07
439.51

hypo
ACTN1
4
42
3.73E−07
116

hypo
TRIM15
4
82
3.79E−07
115.32

hypo
PDZRN3
4
50
9.44E−07
88.29

hypo
COL1A1
4
41
1.26E−06
79.55

hypo
CD93
3
15
2.44E−06
200.26

hypo
ITGA4
3
18
4.52E−06
157.79

hypo
NFE2L3
3
19
7.74E−06
128.74

hypo
HRNBP3
5
189
8.88E−06
25.05

hypo
POMC
3
26
1.00E−05
115.53

hypo
SKAP1
3
27
1.09E−05
111.26

hypo
T
3
31
1.21E−05
106.8

hypo
RHOJ
2
9
2.16E−05
525.33

hypo
COL22A1
3
36
2.26E−05
83.44

hypo
BOC
3
35
2.32E−05
81.15

hypo
SCUBE1
2
23
6.91E−05
273.55

hypo
ROBO4
2
15
7.76E−05
252.46

hypo
HUNK
2
16
8.36E−05
236.68

hypo
AUTS2
3
114
8.36E−05
49.83

hypo
FPR2
2
11
9.00E−05
221.46

hypo
CASZ1
4
174
9.41E−05
21.76

hypo
MEFV
2
11
9.64E−05
200.66

hypo
MXRA8
2
18
9.64E−05
210.38

hypo
ARMC3
2
12
9.64E−05
203.01

hypo
STX1B
2
15
9.64E−05
199.51

hypo
USP54
2
9
9.64E−05
193.85

hypo
PLCH2
3
64
0.000112844
40.89

hypo
FXYD7
2
17
0.000112844
176.04

hypo
INSM1
2
13
0.000113996
169.79

hypo
MYEF2
2
13
0.000113996
169.79

hypo
P2RY6
2
21
0.000156705
142.51

hypo
CA4
2
15
0.000227225
116.31

hypo
AXIN2
2
37
0.000287729
102.35

hypo
SPSB1
2
46
0.000287729
102.78

hypo
KANK4
2
21
0.000316358
95.36

hypo
APCDD1
2
20
0.000419791
81.53

hypo
B3GNTL1
3
158
0.000474472
23.13

hypo
ANGPT1
2
24
0.000585029
67.95

hypo
PRRX1
2
27
0.000625725
64.62

hypo
COL6A1
2
33
0.000696287
60.68

hypo
LRIG1
2
46
0.000726192
59.28

hypo
GLIS1
2
50
0.000828923
54.54

hypo
ST14
2
43
0.000921733
51.33

hypo
SYT7
2
54
0.001010062
48.83

hypo
PHC2
2
34
0.001014634
47.96

hypo
PLXNC1
2
34
0.001014634
47.96

hypo
PKNOX2
2
63
0.001243393
43.29

hypo
ODZ4
2
148
0.001280632
42.51

hypo
MYO7A
2
45
0.001280907
42.08

hypo
EBF2
2
47
0.001382296
40.29

hypo
NXN
3
193
0.002031781
12.67

hypo
PRKAR1B
3
224
0.002535422
11.68

hypo
SYNJ2
2
68
0.002651843
27.84

hypo
MAML2
2
70
0.002780925
27.05

hypo
GAS7
2
72
0.003896102
22.65

hypo
MYT1L
2
170
0.006150038
17.6

hypo
SMOC2
2
164
0.01010976
13.46

hyper
LOC90834
8
11
7.31E−18
375.88

hyper
BRD1
8
42
1.65E−12
98.45

hyper
C6orf25
5
42
1.90E−09
208.6

hyper
PCSK6
7
65
2.09E−09
55.66

hyper
LOC100292680
4
13
2.07E−08
291.99

hyper
PPM1L
5
37
6.18E−08
88.51

hyper
FERMT3
4
21
1.05E−07
180.76

hyper
TES
4
21
3.42E−07
132.58

hyper
PHYHD1
3
9
1.09E−06
316.32

hyper
IGSF6
3
6
1.21E−06
275.53

hyper
UACA
3
22
2.44E−06
238.95

hyper
TNF
4
27
2.66E−06
71.05

hyper
PRMT7
3
24
2.98E−06
219.03

hyper
SEC14L3
3
9
3.07E−06
197

hyper
HSD3B7
3
17
3.07E−06
208.59

hyper
APP
2
19
3.30E−06
2002.59

hyper
MYPN
3
11
3.44E−06
189.82

hyper
HBEGF
3
10
3.74E−06
177.3

hyper
SLC22A1
3
13
3.74E−06
182.93

hyper
LOC100271831
3
9
5.20E−06
151.33

hyper
GPR1
3
14
6.06E−06
149.15

hyper
NINJ2
4
39
6.06E−06
53.01

hyper
GDPD3
3
10
6.90E−06
136.2

hyper
C21orf34
3
16
8.70E−06
130.5

hyper
KHDRBS3
3
17
1.24E−05
115.58

hyper
TRERF1
4
50
1.49E−05
41.35

hyper
COL4A2
5
139
1.53E−05
22.99

hyper
MIRLET7C
2
4
2.05E−05
591

hyper
SPATA18
3
27
3.95E−05
77.34

hyper
SEMA6D
3
22
5.67E−05
65.4

hyper
METTL9
3
25
5.67E−05
66.13

hyper
TIMP2
4
64
5.67E−05
28.37

hyper
KIAA1949
4
100
6.11E−05
27.84

hyper
NRM
2
43
8.35E−05
299.71

hyper
NSMCE2
3
32
0.000105867
51.66

hyper
SLC9A1
3
27
0.000109957
50.44

hyper
C17orf99
2
10
0.000113832
236.4

hyper
MIR1301
2
6
0.000143314
197

hyper
PLXNA2
3
45
0.00015859
43.66

hyper
GALNT12
2
9
0.00018091
176.15

hyper
STX2
3
38
0.000181317
40.8

hyper
CPT1A
3
59
0.000185452
40.31

hyper
EHD4
3
36
0.000185452
39.97

hyper
MYH15
2
14
0.000191884
168.86

hyper
FGL2
2
6
0.000226795
144.6

hyper
RPH3AL
4
154
0.000226795
18.08

hyper
SCARA5
3
39
0.000253629
34.92

hyper
BTC
2
14
0.000270028
135.57

hyper
CETN1
2
11
0.00029116
126.55

hyper
NPL
2
8
0.000332725
113.5

hyper
LARP4
2
20
0.000332725
118.2

hyper
NADK
3
47
0.000334772
30.61

hyper
ITPK1
3
65
0.000345734
30.23

hyper
ZEB2
3
59
0.000346791
30.05

hyper
CCDC25
2
12
0.000360628
106.54

hyper
TMOD4
2
9
0.000360628
106.58

hyper
EGF
2
13
0.000360628
107.08

hyper
SLC1A2
2
32
0.000360628
109.52

hyper
ADCK5
2
22
0.000364838
107.45

hyper
RNF165
2
16
0.000413716
99.09

hyper
CSNK1G2
3
53
0.000425925
27.15

hyper
ERRFI1
2
20
0.000448119
94.9

hyper
ESCO2
2
14
0.000464905
91.32

hyper
CHST11
3
55
0.000464905
26.16

hyper
MUC6
3
56
0.00047946
25.69

hyper
ITGB8
2
13
0.00050411
84.78

hyper
ST5
3
71
0.00050411
24.97

hyper
FANCA
2
28
0.000525004
84.43

hyper
MYF6
2
11
0.00055928
78.87

hyper
SETD1A
2
30
0.000588655
78.8

hyper
RUFY3
2
17
0.000595625
77.05

hyper
MYOM1
2
12
0.000597351
75.67

hyper
ARL4D
2
15
0.000638325
73.47

hyper
NXPH2
2
21
0.000774146
66.29

hyper
MGAT3
2
18
0.000776579
65.67

hyper
AKT3
2
30
0.000841298
63.26

hyper
RELL1
2
23
0.000896152
60.52

hyper
CARS
2
23
0.000896152
60.52

hyper
TRAPPC9
4
215
0.000916221
11

hyper
LZTS1
2
22
0.000916221
59.54

hyper
PPP2R5C
2
59
0.000924708
59.4

hyper
DLX3
2
16
0.000963235
56.75

hyper
AMBRA1
2
28
0.000986075
56.62

hyper
SDCBP2
2
24
0.001039634
54.58

hyper
LMBRD1
2
17
0.00105958
53.41

hyper
ARHGAP1
2
18
0.00106039
53.29

hyper
TBCD
5
352
0.001086318
7.34

hyper
ACSL1
2
30
0.001086318
52.85

hyper
PLCB3
2
26
0.001238237
49.17

hyper
MAP3K1
2
24
0.001394061
45.92

hyper
LRRFIP1
2
76
0.001408026
46.11

hyper
BAI2
2
36
0.001513586
44.04

hyper
ZNRF1
2
26
0.001594799
42.39

hyper
ITGBL1
2
23
0.001628294
41.71

hyper
SPPL2B
2
38
0.001642638
41.72

hyper
PIGV
2
23
0.001779686
39.48

hyper
KLF12
2
40
0.001784969
39.63

hyper
FOXO1
2
32
0.002026288
36.94

hyper
C1QTNF1
2
39
0.002125118
35.69

hyper
NCK2
2
53
0.002125118
35.81

hyper
CYTH1
2
37
0.002143776
35.4

hyper
APOLD1
2
34
0.002203548
34.76

hyper
HTRA1
2
38
0.002233352
34.47

hyper
CCDC146
2
28
0.002665635
30.98

hyper
CRYL1
2
42
0.002665635
31.19

hyper
COL4A1
2
71
0.003503044
26.73

hyper
GPR133
3
165
0.003819221
10.75

hyper
PHACTR2
2
40
0.004172106
23.98

hyper
ANK3
2
38
0.004173533
23.89

hyper
RPTOR
5
432
0.004520935
5.02

hyper
CACNA2D3
2
76
0.005405541
20.86

hyper
LHFPL2
2
44
0.005447591
20.64

hyper
TG
2
47
0.00554287
20.41

hyper
KANK2
2
45
0.005602318
20.18

hyper
SRPK2
2
45
0.005602318
20.18

hyper
PITPNM2
2
48
0.005684708
19.98

hyper
ADAM12
2
52
0.005720838
19.88

hyper
MICAL3
2
47
0.005961209
19.32

hyper
FILIP1L
2
45
0.005961209
19.28

hyper
GALNS
2
73
0.006100028
19.07

hyper
ARHGAP26
2
61
0.006687473
18.07

hyper
ARHGEF7
2
74
0.006937548
17.7

hyper
WIPI2
2
64
0.007267014
17.22

hyper
PTPN14
2
59
0.00801136
16.26

hyper
CUX1
2
215
0.00801136
16.3

hyper
SORBS2
2
81
0.00806007
16.17

hyper
HPCAL1
2
60
0.008172002
15.99

hyper
DNMT3A
2
77
0.00881667
15.35

hyper
TNS3
2
79
0.009173569
14.96

hyper
SLC6A3
2
69
0.009173569
14.98

hyper
PTPRG
2
96
0.01090562
13.64

hyper
MIR548G
2
65
0.01127773
13.35

hyper
ASAP2
2
70
0.01183843
12.97

hyper
C3orf26
2
67
0.01183843
12.95

hyper
NAV1
2
68
0.01212126
12.76

hyper
CREB5
2
82
0.01424866
11.7

hyper
CTBP2
2
102
0.02110821
9.4

hyper
TCERG1L
2
105
0.02218092
9.14

hyper
SHANK2
3
262
0.02489354
4.97

hyper
CMIP
2
113
0.02508337
8.49

hyper
BAT2
2
161
0.02704674
8.14

hyper
EIF2C2
2
117
0.02919953
7.76

hyper
RPS6KA2
2
244
0.02919953
7.78

hyper
PRKCZ
2
263
0.03328032
7.22

Correlation of Gene Expression and Methylation Status

Functional analysis of the differentially methylated was performed by evaluating expression of several representative genes with hypo- and normally methylated loci in RA FLS by qPCR. FIG. 3 shows the results for several hypomethylated genes. These genes included ITGA4, COL1A1, MYEF2, SYNJ2, CHI3L1, STK24, and MAP3K5. As a group, expression of genes with hypomethylated loci was significantly greater in RA than OA FLS (n=7 genes; P<0.01). On the other hand, expression of normally methylated genes was similar in RA and OA FLS (n=7 genes; P>0.10).

Higher expression in RA was demonstrated for most hypomethylated genes, and the differences were significant when the genes were evaluated as a group (P<0.01 for RA vs. OA). Some genes, such as STK24, were not significantly different in RA and could reflect more than methylation in vitro. Nevertheless, these data demonstrated that methylation is reflected in gene expression patterns in RA and could contribute to production of inflammatory mediators in RA.

Pathway and Gene Ontology Analyses

Biological pathways and gene ontologies that are enriched with differentially methylated loci were evaluated. Loci were mapped to pathways via their relationships to genes within pathways for KEGG pathways and for GO using all 1,859 differentially methylated loci identified (TABLE 1). Pathway analysis showed that interactions between cells and the matrix and cell recruitment were especially prominent in the differentially methylated group, including focal adhesion, mTOR signaling, cell adhesion molecules, leukocyte transendothelial interactions, and ECM-receptor interactions. FIG. 4 depicts the pathway ‘Focal adhesion’, which was enriched with loci that are significantly less methylated in RA. A list of differential GO terms and an analysis of hypomethylated and hypermethylated terms in RA with marginal probability>0.5 is shown in TABLE 4.

TABLE 4

Marginal

ID
probability
Name

RA
GO: 0003713
0.99836
Transcription coactivator activity

Hypomethylated
GO: 0051117
0.98512
ATPase binding

GO: 0031519
0.95603
PcG protein complex

GO: 0045944
0.92189
Positive regulation of transcription

from RNA polymerase II promoter

GO: 0019897
0.81989
Extrinsic to plasma membrane

GO: 0008134
0.81119
Transcription factor binding

GO: 0015467
0.78847
G-protein activated inward rectifier

potassium channel activity

GO: 0017157
0.76244
Regulation of exocytosis

GO: 0007369
0.74990
Gastrulation

GO: 0035257
0.70985
Nuclear hormone receptor binding

GO: 0004221
0.59229
Ubiquitin thiolesterase activity

GO: 0004629
0.55446
Phospholipase C activity

GO: 0009897
0.53595
External side of plasma membrane

GO: 0015629
0.52284
Actin cytoskeleton

GO: 0022610
0.51076
Biological adhesion

RA
GO: 0005794
0.77055
Golgi apparatus

Hypermethylated
GO: 0007166
0.76581
Cell surface receptor linked

signaling pathway

GO: 0005488
0.60305
Binding

Of interest, the number of GO terms associated with hypomethylated DNA in RA was greater than for hypermethylated DNA (15 vs. 3). Thus, hypomethylated terms clustered with hypomethylation in RA, especially related to membrane and transcription factor biology. This analysis can be used to identify novel therapeutic targets for RA. More examples of pathways useful to identify novel therapeutic targets for RA are shown in TABLE 5.

TABLE 5

DM

loci
Total

Status

Enrichment
in
loci in

in RA
Path group
Path name
factor
path
path
P-value

hypo
Cell Communication
Focal adhesion
2.615457643
20
6226
0.007005624

hypo
Glycan Biosynthesis
Glycosphingolipid
9.88097044
5
412
0.007005624

and Metabolism
biosynthesis - lacto

and neolacto series

hypo
Cardiovascular
Arrhythmogenic right
3.862390722
10
2108
0.007378046

Diseases
ventricular

cardiomyopathy

(ARVC)

hypo
Signaling Molecules
ECM-receptor
3.303009997
12
2958
0.007378046

and Interaction
interaction

hypo
Infectious Diseases
Amoebiasis
3.278225332
11
2732
0.01087908

hypo
Immune System
Leukocyte
3.339589681
10
2438
0.01366817

transendothelial

migration

hypo
Digestive System
Protein digestion
3.090564183
9
2371
0.03435163

and absorption

hypo
Endocrine System
Adipocytokine
3.505131458
7
1626
0.04363638

signaling pathway

hypo
Signaling Molecules
Cell adhesion
2.542760663
10
3202
0.06198887

and Interaction
molecules (CAMs)

hypo
Energy Metabolism
Nitrogen metabolism
6.691988748
3
365
0.08527128

hyper
Signal Transduction
ErbB signaling
2.295320174
18
2272
0.0580967

pathway

hyper
Infectious Diseases
African
4.05913013
8
571
0.0580967

trypanosomiasis

hyper
Lipid Metabolism
Primary bile acid
5.625639088
4
206
0.0950006

biosynthesis

hyper
Immune System
Fc epsilon RI
2.345183916
13
1606
0.0950006

signaling pathway

hyper
Signal Transduction
mTOR signaling
2.295464506
14
1767
0.0950006

pathway

hyper
Endocrine System
Adipocytokine
2.316337866
13
1626
0.0950006

signaling pathway

Network Analysis

Cytoscape was used to evaluate networks affected by differential methylation and to determine likely targets for subsequent analysis. In a preliminary study, interactions between hypomethylated genes and their neighbors were evaluated. A portion of the Cytoscape analysis is shown in FIG. 5. Significant nodes included key hypomethylated loci (e.g., STAT3, MAP3K5, CHI3L1, STK24) (circle size indicates degree of hypomethylation). FIG. 5 depicts how these loci interact with each other and with multiple additional pathways, and describes how the methylated genes might regulate inflammatory responses in RA. This map shows only a fraction of the interactions and provides an unbiased view of how methylation affects synoviocyte function.

Basal Expression of DNMTs

After discovering that RA FLS are differentially methylated, DNMT expression in resting cultured FLS was examined. Synoviocytes were isolated from RA and OA synovium at the time of total joint replacement. 4^ththrough 6^thpassage cells were evaluated by qPCR. FIG. 6 depicts graphs of relative expression of DNMT1, DNMT3a, and DNMT3b in OA FLS and RA FLS. Unexpectedly, expression levels of DNMTs in RA and OA were found to be similar. In view of these findings, changes in DNMT expression in FLS was examined, and the role of cytokines, e.g., IL-1, in RA, that may contribute to a DNMT profile was examined.

Decreased DNMT1 Gene Expression after IL-1 Stimulation

FLS were stimulated with IL-1 for 24 hr and DNMT expression was determined by qPCR. Unexpectedly, DNMT1 and DNMT3a gene expression significantly decreased after exposure to modest concentrations of IL-1 (FIG. 7). After noting that IL-1 decreased DNMT mRNA, time course experiments were performed to assess the kinetics of the effect. Cells were stimulated with 1 ng/ml of IL-1 for various time periods and qPCR was performed. DNMT mRNA levels begin to decrease within 2 to 8 hrs after exposure to the cytokine (data not shown).

IL-1 Decreases DNMT Function in FLS

A functional assay was performed to determine if IL-1 suppresses DNA methylation activity of the DNMTs. FLS were stimulated with 1 ng/ml of IL-1 for 14 days and extracts were assayed using the DNMT Activity/Inhibition Assay (Active Motif Co., Carlsbad, Calif.), which is an ELISA-based method that measures methylation of a CpG-enriched DNA substrate. As shown in FIG. 8, a significant decline in total DNMT function (p<0.05) was observed.

Discussion

FLS form the synovial intimal lining and play an integral role in the pathogenesis of RA by producing key cytokines, small molecule mediators, and proteases. While osteoclasts are the primary effectors of bone erosions in arthritis, FLS are responsible for cartilage damage by virtue of their ability to adhere to and invade the cartilage extracellular matrix. This capacity requires homotypic aggregation mediated by the adhesion molecule cadherin-11, which directs intimal lining formation and supports an invasive phenotype. Understanding the molecular mechanisms that regulate FLS activation could provide insights into the pathogenesis of RA and lead to novel therapeutic strategies. In the present application, the epigenetic profile of RA was evaluated by exploring a newly discovered DNA methylation signature that could potentially affect adaptive and innate immune functions, through their effects on synoviocytes and immune cells in the blood and joint.

Rheumatoid FLS exhibit a unique aggressive phenotype that contributes to the cytokine milieu and joint destruction. Functional studies suggest that RA cells are imprinted in situ and maintain these features after many passages in tissue culture. For example, RA FLS, unlike OA or normal synoviocytes, adhere to and invade cartilage explants in SCID mice. RA FLS can grow under anchorage-independent conditions, are less susceptible to contact inhibition, resistant to apoptosis. RA synoviocytes can potentially “metastasize” and transfer the invasive phenotype from one joint to another.

Several mechanisms have been implicated in this persistently aggressive phenotype, including abnormal sentrin or PTEN expression, preferential shunting of stressed cells to DNA repair rather than programmed cell death., and somatic mutations of regulatory genes. Microsatellite instability has also been identified in RA synovium, in part due to decreased DNA repair. These genetic modifications potentially serve to amplify disease severity.

While the focus on gene sequences in FLS and in disease association studies has provided important insights, other mechanisms can change cell phenotype. Epigenetics, for instance, can profoundly influence cell activation and gene expression through a variety of mechanisms, including DNA methylation, histone modification, and microRNA production. DNA methylation could be especially relevant in RA, in light of role in neoplasia and embryonic growth. Normal ontogeny relies on a carefully orchestrated sequence of DNA methylation to repress regulatory genes by methylating cytosine in CpG loci, either in promoters or in genes themselves. Methylation abnormalities have been associated with many diseases, most notably cancer where renewed expression or inappropriate suppression of genes allows cells to escape normal homeostatic controls. Hypomethylation and hypermethylation are associated with many malignancies and can contribute to transformation.

DNA methyltransferases (DNMTs) are responsible for initiating and maintaining CpG methylation in the human genome by converting cytosine to methylcytosine. In mammalian cells, DNMT1, DNMT3a, and DNMT3b are the primary enzymes responsible for CpG methylation. DNMT3a and DNMT3b mainly regulate de novo methylation while DNMT1 maintains methylation, especially during cell division. DNMT expression and DNA methylation are not immutable but are influenced by the environment and modify gene expression throughout life and even in progeny. For instance, pregnant mice fed a diet rich in methyl donors give birth to pups with increased levels of DNA methylation and increased airway reactivity in murine asthma for at least two subsequent generations.

Global hypomethylation has been described in peripheral blood mononuclear cells of patients with RA, although the specific genes involved are not known. Modest global hypomethylation was also reported in cultured RA FLS when compared to OA cells. In contrast, our studies showed that global methylation levels are similar in OA and RA FLS using two different techniques (ELISA-based and chip based). Thus, RA FLS do not appear to be hypomethylated overall, but like neoplasia, display a pattern of hypermethylated and hypomethylated genes.

The ILLUMINA chip analysis identified distinct methylation profiles of OA and RA FLS involving 1859 loci located in 1206 genes. Cluster analysis showed that the two types of FLS could be easily distinguished based solely on the methylation patters. The results were confirmed using a variety of additional analyses that reduced the possibility of random chance as an explanation. Additional analysis identified 207 genes with multiple hyper- or hypomethylated loci. Many of these genes play a key role in inflammation, matrix regulation, leukocyte recruitment and immune responses. Gene expression levels correlated with methylation status, with high expression in hypomethylated genes in RA FLS and normal expression in genes that were not differentially methylated. Given the number of influences that can potentially alter gene expression in vitro, the general concordance between methylation and mRNA levels was striking.

The data described herein provide evidence that epigenetic changes are present in RA synoviocytes and that they persist in culture. Imprinting could potentially occur before clinical disease and contribute to susceptibility. Alternatively, and perhaps more likely, the changes can be induced after initiation of synovitis. In the latter situation, the inflammatory milieu could potentially imprint synoviocytes and affect their function for many passages. Thus, local inflammation could potentially alter expression of enzymes responsible for initiating and maintaining DNA methylation. This process imprints synoviocytes, peripheral blood cells that are present in synovium for a short period of time, and immune cells, alters their behaviour, and ultimately changes the natural history of disease.

The ability to distinguish RA and control cells based solely on the DNA methylome could provide major insights into how the epigenetic profile of various tissues contribute to the pathogenesis of RA. In addition to identifying novel targets among the differentially methylated genes, it could also lead to interesting diagnostic or personalized medicine applications after sufficient data are available to correlate the methylome to phenotype.

Example 2
Methylation of Loci in Peripheral Blood Cells

Isolation of Genomic DNA from Peripheral Blood Cells

Approximately 6-8 ml of blood was drawn into a DB CPT tube (BD cat#362760) and inverted 10 times. Four tubes per patient were drawn. The tubes were stored at room temperature until processed. Processing was performed in less than four hours after being drawn. The tubes were spun 30 minutes at 3000 rpm. The mononuclear cell layer was carefully removed and washed in at least 10 volumes of cold PBS with 0.1% BSA (Buffer 1: PBS Invitrogen cat#14190, BSA Gemini cat#700-100P). Mononuclear cells were then spun at 1600 rpm for 10 minutes. Cells were then resuspended in 3 ml of cold PBS supplemented with 0.1% BSA and 2 mM EDTA (Buffer 2: Buffer 1 plus EDTA Invitrogen cat#15575020). Cells were then counted and divided into 2 ml eppendorf tubes as follows: 0.5 ml for T-cell isolation, 1.5 ml for B-cell isolation, 0.75 ml for monocyte isolation, and 0.25 ml for whole PBMCs. These were spun again at 1600 rpm for 10 minutes and supernatants were discarded. The whole PBMC fraction was frozen while the others continued the specific cell type separation.

Separation of PBMCs into Specific Cell Types

Cells in the PBMC preparation above were separated into B cell preparations, T cell preparations and monocyte preparations as follows. Dynabeads magnetic beads (CD19 pan B Invitrogen cat#111-43D, CD2 pan T Invitrogen cat#111-59D, CD14 monocyte Invitrogen cat#111-49D) were used for the specific cell-type isolation. The magnetic bead mixtures were added to 1 ml of cold Buffer 2 according to the number of cells (50 μl T-cell bead isolation mixture per 10⁷cells, 25 μl B-cell bead isolation mixture per 2.5×10⁷cells, and 25 μl monocyte isolation bead mixture per 10⁷cells), mixed well and applied to the magnet for 3 minutes to wash the beads. Supernatants were discarded. Mononuclear cell pellets were then gently resuspended in 1.5 ml of cold buffer 2 and added to their appropriate bead isolation mixture. The bead/cell mixture was incubated at 4° C. while turning end-over-end for 20 minutes. The bead/cell mixture was then applied to the magnet for 3 minutes and supernatants were discarded. The bead/cell mixture was then washed 3 times by removing from the magnet, adding 1 ml cold Buffer 2, gently mixing, reapplying to the magnet, and discarding the supernatant. The cell/bead mixture was then frozen until DNA Isolation was performed. The DNA isolation was performed with DNeasy Blood and tissue Kit (Qiagen cat#69504). The protocol for cultured cells was followed and included the recommendation of RNase A (Qiagen cat#19101) treatment. DNA eluents were then concentrated using Amicon ultra 30K filers (Millipore cat# UFC503096). Concentrated DNA was then quantified using Quant-it Picogreen reagent (Invitrogen cat# P7589). Concentrations were then standardized to 100 ng/μl.

PBMC preparations may also be separated into other cell types, such as white blood cells, neutrophils, eosinophils, basophils, lymphocytes, plasma cells, natural killer cells, and dendritic cells using procedures such as those described above or other methods familiar to those skilled in the art. Macrophages may be separated from other cell types using methods well known in the art. In some embodiments, particular cell types can be enriched and/or isolated using a variety of methods, such methods are well known in the art and include immunological methods, fluorescent activated cell sorting (FACS) methods, and affinity chromatography methods. For example, cells such as eosinophils can be enriched/isolated using antibodies specific to specific receptors on the cell surface such as L-selectin, and VLA-4 (Sriramarao P., et al., (1994) J. Immunol. 153:4238-46, incorporated by reference in its entirety) Neutrophils may be isolated using density gradients or using antibodies specific to other cell surface receptors (Firestein G. S., et al., (1995) J. Immunol. 154:326-34, incorporated by reference in its entirety).

Analysis of Methylation States of Loci in PBMCs or Specific Cell Types Separated from PBMC Preparations in Individuals with RA or OA

Samples of genomic DNA are obtained from peripheral blood mononuclear cells or specific cell types separated from PBMC preparations as described above. The samples are obtained from individuals with RA, individuals with OA, individuals with a known prognosis for rheumatoid arthritis or osteoarthritis, individuals with a known reponse to treatment for rheumatoid arthritis or osteoarthritis and control subjects without rheumatoid arthritis, without osteoarthritis, without the known prognosis for rheumatoid arthritis or osteoarthritis, or without the known response to treatment for rheumatoid arthritis or osteoarthritis using methods described herein. The methylation states of loci for each set of genomic DNA is determined as described herein for genomic DNA from FLS cells.

Hypomethylated and hypermethylated loci in individuals with RA, individuals with OA, individuals with a known prognosis for rheumatoid arthritis or osteoarthritis, individuals with a known response to treatment for rheumatoid arthritis or osteoarthritis are identified by comparing the methylation states of the loci to the methylation states of the loci in control subjects without rheumatoid arthritis, without osteoarthritis, without the known prognosis for rheumatoid arthritis or osteoarthritis, or without the known response to treatment for rheumatoid arthritis or osteoarthritis respectively using the methods described herein for FLS cells.

In some embodiments, hypomethylated and hypermethylated loci in RA genomic DNA relative to the methylation state of loci in OA genomic DNA are identified. In other embodiments hypomethylated and hypermethylated loci in RA genomic DNA relative to the methylation state of loci in genomic DNA from control subjects without RA are identified. In some embodiments, hypomethylated and hypermethylated loci in OA genomic DNA relative to the methylation state of loci in genomic DNA are identified from control subjects without OA are identified.

Genes with multiple differentially methylated loci are analyzed as described herein for genomic DNA from FLs cells, Gene expression and methylation status are analyzed as described herein for genomic DNA from FLs cells, Pathway analyses and gene ontology analyses are performed as described herein for genomic DNA from FLs cells. Network and DNMT analyses as described herein for genomic DNA from FLs cells.

Example 3
Evaluation of a Subject for RA,OA, Individuals with RA, a Particular Prognosis for Rheumatoid Arthritis or Osteoarthritis, or a Particular Response to Treatment for Rheumatoid Arthritis or Osteoarthritis

Genomic DNA is obtained from a subject and the methylation states of one or more loci having differential methylation in individuals with individuals with RA, individuals with OA, individuals with a particular prognosis for rheumatoid arthritis or osteoarthritis, or individuals with a particular response to treatment for rheumatoid arthritis or osteoarthritis is determined.

In some embodiments, the methylation state of the one or more differentially methylated loci in the genomic DNA from the subject is compared with the methylation state of the one or more differentially methylated loci in normal tissue, tissue from a subject with a known prognosis, or tissue from a subject with a known response to treatment. In other embodiments, the methylation state of the one or more differentially methylated loci in the genomic DNA from the subject is compared with a methylation state of the one or more differentially methylated loci known to be indicative of RA or a lack thereof, OA or a lack thereof, a particular prognosis for rheumatoid arthritis or osteoarthritis or a lack thereof, or a particular response to treatment for rheumatoid arthritis or osteoarthritis or a lack thereof.

The genomic DNA may be obtained from any desired cell type, including the cell types listed herein. For example, the genomic DNA may be obtained from FLS cells, a peripheral blood sample or a specific cell type separated from a PBMC sample obtained from a subject. If the methylation state of the one or more differentially methylated loci is a methylation state known to be indicative of RA, a particular prognosis for rheumatoid arthritis or osteoarthritis, or a particular response to treatment for rheumatoid arthritis or osteoarthritis the subject is determined to have RA, the particular prognosis for rheumatoid arthritis or osteoarthritis, or the particular response to treatment for rheumatoid arthritis or osteoarthritis. A treatment regimen consistent with this determination may then be administered.

Example 4
Evaluation of a Methylation State of Loci in Control Subjects Compared to Methylation State of Loci in RA FLS and OA FLS

Genomic DNA is obtained from a subject without RA and a subject without OA and the methylation states of one or more loci having differential methylation in RA FLS and OA FLS cells, respectively, is determined.

In some embodiments, the methylation state of the one or more differentially methylated loci in RA FLS and OA FLS cells is compared to a methylation state of the one or more differentially methylated loci in the genomic DNA from a subject without RA and in the genomic DNA from a subject without OA, respectively. In some embodiments, the methylation state of loci indicative of the absence of RA or OA in a subject are determined.

Example 5
Evaluation of Methylation State of Loci in Peripheral Blood Mononuclear Cells (PBMCs)

The methylation states of loci in PBMCs were determined with methods substantially similar to those described herein using the ILLUMINA HumanMethylation 450 BeadChip. Differentially methylated loci (DML) were identified with average methylation differences between OA and RA of >0.10. RA/OA differential methylation was conducted using a t-test. P-values were converted to q-values to account for multiple hypothesis testing, and DML with q-values<0.25 were considered to be potential PBMC biomarkers. TABLE 8 lists about 2544 RA/OA PBMC DML with associated data including the OA-RA average methylation difference, CG identifier associated with the Illumina 450K beadchip (Locus), associated genes, and the genomic location of the potentially methylated C of the CpG (+ strand) determined using the UCSC hg19 reference genome. The CpG* column of Table 8 lists values for “chromosome:chromosome co-ordinate.”

TABLE 6

OA −

SEQ

RA
Locus
Associated gene
ID No.

0.39071
cg20114732
T
361932

0.37096
cg03044684
HUNK
62005

0.36569
cg20824939

372791

0.36469
cg19081101
CHI3L1
345293

0.36368
cg13225830

243918

0.36153
cg27244773
ARHGAP27; ARHGAP27;
475250

ARHGAP27

0.34388
cg02792136
DIP2C
56847

0.33702
cg12557114
WISP3; WISP3
233566

0.33333
cg06043820
ZNF592
119061

0.33296
cg07804470
STK24
151872

0.33037
cg12578486
UBAC2; UBAC2; UBAC2
233879

0.32914
cg18886274

342488

0.32889
cg12651286
MMP20
235219

0.32591
cg10035831
RPTOR; RPTOR
191245

0.32183
cg12476044
EGFLAM; EGFLAM; EGFLAM;
232241

EGFLAM; EGFLAM

0.32154
cg16214653

298250

0.32018
cg06550177

127813

0.31828
cg06357305
PTGIS
124318

0.31549
cg27250435

475334

0.31524
cg24203758
SH3D20
425444

0.31391
cg18675043
SH3PXD2A
338965

0.30767
cg11173579
HUNK
210693

0.30665
cg21514164

383094

0.30602
cg21670717

385687

0.30248
cg09182085

176526

0.30113
cg09230154
MACF1; MACF1
177251

0.30097
cg27642470
DCBLD1
482028

0.2993
cg23413809
SIX2
412582

0.29885
cg07474842
MAP3K5
1415804

0.29665
cg23004031
MGMT
405673

0.29622
cg02727484
KCNMA1; KCNMA1; KCNMA1;
55565

KCNMA1

0.29494
cg07227049
VRK2; VRK2; VRK2; VRK2;
141396

VRK2; VRK2

0.28978
cg06223539
SHANK2
122219

0.28958
cg19674091
IDH2
354510

0.28897
cg06966660
TACC2; TACC2; TACC2; TACC2
136119

0.28527
cg22778178

401834

0.28511
cg12427162
SFT2D2
231416

0.28455
cg16854917
NCRNA00085
309652

0.28177
cg03834767
CDK14
77306

0.28129
cg17820022
PLCH2
324801

0.27987
cg05040219
GLIS1
100492

0.27931
cg00807684
RBMS3; RBMS3; RBMS3
17055

0.27912
cg10536999
NFE2L3
200194

0.27826
cg22458832

396980

0.2773
cg09257635
GJC2
177820

0.27706
cg24576026
SEPT9; SEPT9
431206

0.27474
cg01999051
BRP44L
40997

0.27386
cg10820084
COL1A1
204937

0.27361
cg07696516
LIMCH1; LIMCH1; LIMCH1;
149907

LIMCH1; LIMCH1; LIMCH1;

LIMCH1

0.27349
cg10937408
HRNBP3
206779

0.2732
cg07021447
ACTN1; ACTN1; ACTN1
137188

0.27261
cg13644549
C7orf50; C7orf50; C7orf50
252081

0.27247
cg26787787

467264

0.27222
cg10881749

205937

0.27192
cg24718015
STAT3; STAT3; STAT3
433677

0.27022
cg03780701
ADAM32
76382

0.26961
cg13735018
SYNJ2
254007

0.26932
cg19391924
HRNBP3
349887

0.26888
cg13551141
PSMB7
250097

0.2674
cg14370520
FAM188B
267054

0.26591
cg01660999
ANGPT1
34240

0.26415
cg13626830
RASGRF2
251743

0.26352
cg20441502
FXYD7; FXYD1; FXYD1
366782

0.26348
cg01833196
SH3PXD2A
37634

0.26334
cg00369056

7795

0.26334
cg13683667

252916

0.26327
cg19576241

352883

0.26302
cg21983607

390212

0.26214
cg03666350

74131

0.26137
cg05166871
SKAP1; SKAP1
102879

0.2612
cg15366684
ADAMTS2; ADAMTS2
284322

0.26116
cg25885684

451999

0.26059
cg17290488
C5orf45; C5orf45
316572

0.25763
cg19954341
T
359498

0.25735
cg20668662
SH3PXD2A
370194

0.25696
cg24657523
MYEF2
432522

0.25675
cg03537386
COL16A1
71519

0.25598
cg25616600

448034

0.25566
cg20201270

363196

0.25559
cg01229787

25802

0.25515
cg08145723
ST14
158133

0.25468
cg07878514
INSM1; INSM1
153203

0.25399
cg06189394
LRIG1
121568

0.25382
cg08830502

170348

0.25298
cg05979619
MERTK
117911

0.25278
cg16402635
CASP1; CARD16; CASP1; CASP1;
301579

CASP1; CASP1; CARD16

0.25223
cg17007374

311924

0.25189
cg26681770
PMEPA1; PMEPA1; PMEPA1;
465572

PMEPA1

0.25166
cg04649852

92984

0.25103
cg16282024
DERL1; DERL1
299433

0.25043
cg01392518
T
28927

0.24945
cg05590156
TRIO
110699

0.24922
cg24174557
TMEM49
425007

0.24886
cg00225902
LRIG1
4852

0.24875
cg03401875
ADAMTS2; ADAMTS2
68835

0.24859
cg23489226

413717

0.24854
cg15745401
P2RY6; P2RY6
290636

0.24785
cg24752267

434286

0.24696
cg09527270
POMC; POMC
182597

0.24687
cg00145961
NTRK3; NTRK3; NTRK3
3269

0.24685
cg15323840
SYNJ2
283724

0.24679
cg11261412
B3GNTL1
212263

0.24671
cg04723534
C2CD2
94311

0.2467
cg03771840
TRIM15
76209

0.24643
cg03472954
PRKAR1B; PRKAR1B; PRKAR1B;
70250

PRKAR1B; PRKAR1B; PRKAR1B

0.24643
cg23533513
MYO7A; MYO7A; MYO7A
414506

0.24628
cg19010441
MED12L; GPR171
344302

0.24604
cg06186245
TMEM45A
121509

0.24529
cg23834919

419111

0.24525
cg00037856

943

0.24513
cg27338607

476928

0.24455
cg05287372
C3orf64
105151

0.24329
cg14905634
TRHDE
277082

0.24298
cg11692307
PLCH2
219166

0.24275
cg04677410
MAML2
93491

0.24251
cg16561266
LOC146880; LOC146880
304457

0.24244
cg09461792

181455

0.24119
cg00548708

11644

0.24101
cg11120154

209834

0.24078
cg14587335
HRNBP3
271586

0.23936
cg09650180
GMEB2
184694

0.23799
cg09379935
P2RY6; P2RY6
180013

0.23797
cg21680719
FHL3
385790

0.23791
cg24917131

437034

0.23723
cg12097883
LOC146880; LOC146880
226317

0.23698
cg03558269

71975

0.2367
cg08870914

171157

0.23667
cg14501219
LOC146880; LOC146880
269672

0.2365
cg09180564
OLFM3
176500

0.23608
cg02477603

50448

0.23603
cg14260695

264921

0.23574
cg08613122
PRKAR1B; PRKAR1B; PRKAR1B;
166544

PRKAR1B; PRKAR1B; PRKAR1B

0.23559
cg25577130
CA4
447341

0.23548
cg08718098

168443

0.23462
cg17896243

326150

0.23435
cg09385667
PDZRN3
180096

0.2343
cg09529093
ANGPT1
182630

0.23254
cg10960920
PGCP
207207

0.23124
cg07107756
CARD14; CARD14
138866

0.23111
cg07480647
GPR153
145935

0.23044
cg11218619

211494

0.23008
cg05721365
LOC146880; LOC146880
113082

0.22965
cg21531685
PDZRN3
383375

0.22946
cg12854371
LOC146880; LOC146880
238254

0.22905
cg04028695

81035

0.22873
cg05665651
ANKRD11
112125

0.22861
cg09259235

177859

0.2273
cg15341866

283990

0.22729
cg03019360

61484

0.22691
cg19409546

350194

0.22689
cg26098164
BMP7
455309

0.22559
cg23965931
STOX2
421288

0.22486
cg27292547

475989

0.22459
cg10094238
ARHGAP27; ARHGAP27;
192273

ARHGAP27

0.22433
cg26938118
NEDD4L; NEDD4L; NEDD4L;
470085

NEDD4L; NEDD4L; NEDD4L;

NEDD4L; NEDD4L; NEDD4L

0.22395
cg12741645
AEN
236560

0.22392
cg11189268
ARHGAP27; ARHGAP27
210952

0.22268
cg10481134
C2orf58
199061

0.22247
cg25213720
MXD3; MXD3
441707

0.22232
cg07357716

143726

0.22207
cg10975897
JARID2
207446

0.22204
cg10177197
DHCR24
193879

0.22183
cg26215428
PKD2
457374

0.2215
cg01451808

30240

0.22132
cg24186459

425188

0.2211
cg14910684

277182

0.21926
cg01040786

21929

0.21871
cg07146912
PDZRN3
139702

0.21843
cg01359469
TRIP4
28275

0.2181
cg07459478
VOPP1
145466

0.21793
cg06012804

118540

0.21771
cg25335841

443510

0.21765
cg26303870
ACTN1; ACTN1; ACTN1
458957

0.21683
cg01095004

23112

0.21596
cg13369952
JAKMIP2
246290

0.21555
cg26159368

456463

0.21526
cg10328583
PLEKHG5; PLEKHG5; PLEKHG5;
196553

PLEKHG5

0.21524
cg22041190
PKNOX2
391040

0.21505
cg13717446
LOC146880; LOC146880
253646

0.215
cg20134287
AUTS2; AUTS2
362245

0.21488
cg16755214

308115

0.21465
cg00599219
MEFV
12810

0.21458
cg13470462
BOC
248426

0.21391
cg13027183
JARID2
240842

0.21382
cg14467181

268995

0.21371
cg04674201

93425

0.2137
cg16936561
RAB11FIP5
310943

0.21339
cg13393580
MXRA8
246755

0.21294
cg00813162
ACTN1; ACTN1; ACTN1
17174

0.21281
cg21687563
TTC28
385895

0.21199
cg07076816

138253

0.21196
cg10195336
ARHGEF10
194213

0.21167
cg26588688

463998

0.21129
cg14524975
ITGB7
270223

0.21125
cg05373161
TMEM231; TMEM231; TMEM231
106877

0.21109
cg10283505
FUT4; FUT4
195763

0.2109
cg27190145
DAAM2
474406

0.21048
cg23403980
SMG6; SMG6
412406

0.21047
cg10734665
ATP10A
203498

0.2102
cg01071185

22591

0.20996
cg13313047
CABLES1; CABLES1; CABLES1
245295

0.20986
cg18325315
GTF2IRD1; GTF2IRD1
333329

0.2097
cg24478420

429606

0.20967
cg20489026
KCNJ9
367521

0.20958
cg09119854
AXIN2
175345

0.2095
cg02186748
COL1A1
44750

0.20938
cg08223717
EEPD1
159595

0.20902
cg17265829
FAT4
316130

0.20884
cg04158862
KIAA0247
83588

0.2087
cg01521220
MIR1203; SKAP1; SKAP1
31528

0.20851
cg20472384
DIP2C
367281

0.2085
cg01322214
C7orf31
27599

0.20824
cg22972806
LYPD6B
405136

0.20805
cg12531838
DIP2C
233187

0.20773
cg06946797

135711

0.20742
cg11394820

214445

0.2069
cg06132400

120606

0.20684
cg13505393
LRRC32; LRRC32
249183

0.20661
cg02931762

59687

0.20651
cg23367392
GLI3
411874

0.20651
cg21699330
NFE2L3
386040

0.20618
cg09532095
THUMPD2; THUMPD2
182672

0.20597
cg02955287

60173

0.20575
cg07980854

155098

0.20548
cg21838924
CLDN4
388015

0.20493
cg09703910

185605

0.20481
cg03179435
FRMD4A
64565

0.20458
cg25946605
CYS1
452893

0.20455
cg12473775
RHOD
232200

0.20401
cg05467716
LOC146880
108495

0.20331
cg18476176
CNTF; ZFP91-CNTF
335848

0.20322
cg18362448
SSBP4; SSBP4
333911

0.20314
cg19245980

347655

0.20291
cg27342781

476987

0.20279
cg08011255
B3GNTL1
155601

0.2027
cg25252585
FXYD7
442281

0.20218
cg08170227
ACTN1; ACTN1; ACTN1
158605

0.20196
cg01700462
C20orf123
34874

0.20185
cg08920174

172096

0.20181
cg06180729
LDLRAD3
121411

0.20165
cg03144232
STX1B
63872

0.20053
cg05302100
COL1A1
105438

0.20037
cg01572653

32559

0.20024
cg00509485

10852

0.20012
cg02077068
GPRC5B
42649

0.19965
cg08797704

169751

0.19946
cg25674613

448920

0.19907
cg14236519
C7orf50; C7orf50; C7orf50
264409

0.19873
cg09371059

179858

0.19866
cg07250758
VWCE
141804

0.19825
cg14463068
MYT1L
268912

0.19821
cg27638057
C18orf45
481936

0.19814
cg19764489
KCNQ1; KCNQ1
356206

0.19799
cg05501859
C11orf17; C11orf17
109151

0.19792
cg02108623
PRDM1
43306

0.19791
cg18229049
NXN
331759

0.1975
cg15557036

287330

0.19749
cg03284879

66524

0.19681
cg23899450

420132

0.19665
cg16896313

310257

0.19654
cg11738198

219981

0.19638
cg25104234

439983

0.19612
cg08863777
FUT4
171018

0.19591
cg03143849
CDKN1C; CDKN1C; CDKN1C
63866

0.19551
cg27608563
CMIP
481430

0.19548
cg15601264

288057

0.19518
cg25712088
DIP2C
449437

0.19493
cg14003265
TRAF2
259423

0.19481
cg16926213

310774

0.19467
cg15339026

283944

0.19466
cg16429975
ACOT7; ACOT7
302121

0.19451
cg19780308
MAML3
356489

0.19435
cg01741688
SH3RF3
35665

0.19412
cg15465501

285947

0.19412
cg08639948

167048

0.19403
cg12453623

231887

0.19394
cg19093370
PLD6
345512

0.19388
cg10331829
SLC1A2
196611

0.19382
cg01806382

37024

0.1935
cg20953052
MIR548F2; ERBB4; ERBB4
374498

0.19341
cg20917077
CPA5; CPA5; CPA5
373937

0.19321
cg16434331
SLC39A11; SLC39A11
302207

0.19286
cg06581409

128362

0.1925
cg13229078

243978

0.19228
cg07044938

137615

0.19221
cg22853713
CASZ1; CASZ1
403146

0.19142
cg23878906

419768

0.19138
cg10469520

198872

0.19133
cg24229188
HMG20B
425784

0.19107
cg27185501

474347

0.19077
cg03556869
UST
71956

0.19047
cg03179447

64567

0.18988
cg15457718

285805

0.18981
cg27169559

474039

0.1897
cg00660305
PRKAR1B; PRKAR1B; PRKAR1B;
13970

PRKAR1B; PRKAR1B; PRKAR1B

0.1891
cg20142501
NXN
362369

0.18892
cg15298286
C17orf72
283380

0.18871
cg25954269

453043

0.18845
cg25418528
P2RX6; P2RX6
444919

0.18829
cg27132535

473446

0.18828
cg15449664
THY1
285660

0.18804
cg09109656

175197

0.18788
cg04070601
FMNL3; FMNL3
81748

0.18776
cg20882260
CACNA1C;
373464

0.18756
cg18267489
CD93
332434

0.1875
cg20463302
SH3D20
367133

0.18746
cg22020227
OLFML3
390677

0.18628
cg11419575

214920

0.18581
cg23369564
PLEKHO1
411901

0.18537
cg04768998
WIPF1; WIPF1
95158

0.18526
cg06605053

128746

0.18519
cg05008070
DACT1; DACT1
99885

0.18519
cg16030113

295289

0.18514
cg00472879
SORBS1; SORBS1; SORBS1;
10022

SORBS1; SORBS1; SORBS1;

SORBS1

0.18466
cg14832378

275849

0.18464
cg27438889
TACC2; TACC2; TACC2; TACC2
478571

0.18403
cg04098052

82284

0.184
cg26275647
MDFIC; MDFIC
458453

0.18384
cg05757757

113669

0.18333
cg01198994
MXRA8
25206

0.1833
cg16104139

296436

0.18322
cg09868374

188450

0.18317
cg17797591
AXIN2
324404

0.18247
cg00250409

5354

0.18239
cg09976669
SWAP70
190212

0.18236
cg22231400
SLC17A7
393823

0.18227
cg02351674

48045

0.18188
cg11676636
ARHGAP22
218912

0.18152
cg00831127
EPHB2; EPHB2
17525

0.18147
cg14054883
SYK; SYK; SYK; SYK
260571

0.1814
cg05147262
ENAM
102478

0.1812
cg21242079
ADAMTS7
379397

0.18059
cg26523175
PDZK1IP1
462775

0.18031
cg04778236
SPSB1
95348

0.18026
cg01820962
NT5DC1
37371

0.18025
cg12315995

229820

0.17993
cg17250262
LBH
315917

0.17965
cg14227785

264238

0.17877
cg10882304
TACC2; TACC2; TACC2; TACC2
205944

0.17828
cg07047570
INSM1; INSM1
137657

0.17808
cg07286123
CD93
142424

0.17794
cg14089493

261291

0.17787
cg07997634
SLC25A13; SLC25A13; SLC25A13
155378

0.1776
cg18628732

338265

0.17747
cg12239557
TACC2; TACC2
228662

0.17737
cg06376402
INPP5A
124706

0.17726
cg09642857

184563

0.17704
cg17099048
COL22A1
313414

0.17689
cg10819733

204928

0.17667
cg26477792

462022

0.17575
cg00373436
TAGLN3; TAGLN3; TAGLN3
7897

0.17567
cg15029402

279170

0.17558
cg19080233

345285

0.17527
cg00157016
PFN4
3525

0.17525
cg02278646
ANO6; ANO6; PLEKHA9; ANO6
46492

0.17489
cg14684457
NFE2L3
273413

0.17474
cg09125999
DSCAML1
175477

0.17462
cg04940251

98587

0.17444
cg07135032
LMX1A
139425

0.17437
cg03491895

70579

0.17348
cg07459019

145455

0.17324
cg03762242
GAS7; GAS7; GAS7
76010

0.17305
cg23585686

415170

0.17287
cg00400827

8476

0.17285
cg02284273
FRMD4A
46611

0.17232
cg03560973
POMC; POMC
72034

0.17213
cg22304543

394846

0.17212
cg24147392
LOC440461
424521

0.17206
cg14251267
ZBTB46
264704

0.1718
cg20052079
JARID2
360990

0.17144
cg19161251
LMO4
346462

0.17138
cg01364478
PRRX1; PRRX1
28365

0.17129
cg14255700
IPPK
264808

0.17113
cg07067577
SH3D20
138069

0.17078
cg27345989
NXN
477039

0.17062
cg21029769
ST14
375731

0.17054
cg26821721
KLHL29
467947

0.17025
cg13890428

257013

0.17003
cg15134506
USP54
280991

0.17002
cg21142398
GLIS1
377429

0.16954
cg08533336
USP2; USP2
165172

0.16947
cg18006637
FAM13A; FAM13A
327818

0.16924
cg23692500

417116

0.16901
cg01093786
MAML2
23085

0.169
cg00285394
SQLE
6012

0.16825
cg20673819
C6orf176; C6orf176
370286

0.16804
cg03676578

74324

0.168
cg21946195
ATOH8
389751

0.16791
cg10346364
LOC100130987; CLCF1; CLCF1
196856

0.16785
cg08935841

172361

0.16779
cg02216727
GJD3; GJD3
45257

0.16775
cg13088556

241806

0.16685
cg20860726
MYT1L
373230

0.16671
cg11927233
NPM1; NPM1; NPM1
223346

0.16655
cg17842189
TBC1D22A
325238

0.16649
cg23508201

414035

0.16631
cg18772205
KLHL6
340567

0.16625
cg18402987

334557

0.16616
cg10350880
EPHB4
196929

0.16606
cg03943115
SPRR2D
79303

0.16531
cg03967266

79784

0.16529
cg09099242
MMRN2
175043

0.16453
cg08302650
LRRC24; LRRC14
161144

0.1644
cg08049717
AMOTL2
156270

0.16429
cg03764092
TBXAS1; TBXAS1; TBXAS1;
76037

TBXAS1; TBXAS1; TBXAS1

0.16421
cg07275179
ATXN7; ATXN7
142217

0.16413
cg05529123

109677

0.16411
cg14103872
OLFML2A
261610

0.16404
cg19996406

360145

0.16364
cg16568084

304587

0.16364
cg13165983

242911

0.16332
cg00409696

8667

0.16319
cg11733958
MPRIP; MPRIP
219898

0.16308
cg08458711
BSND
163781

0.16261
cg18861112
WDFY2
342032

0.16254
cg21293455

380108

0.16247
cg06526620
FUT4
127302

0.16242
cg12303623
USP54
229638

0.16225
cg06501835

126864

0.16225
cg05243389
MYEF2
104339

0.1619
cg15372959
TACC2; TACC2; TACC2; TACC2
284406

0.16187
cg08879365

171347

0.16183
cg00802386

16940

0.16175
cg16224163
LPP
298398

0.16119
cg02276070
ARSI
46431

0.16116
cg00702126
VWA1; VWA1
14846

0.1611
cg04674421

93433

0.16107
cg08333931
SH3D20
161705

0.16089
cg27177158

474183

0.16083
cg04948016

98755

0.1607
cg19144071

346231

0.1607
cg10628617
SCUBE1
201790

0.16063
cg19542987
ARMC3
352374

0.16049
cg27265404

475561

0.16007
cg03756522

75895

0.15976
cg19856845
RIN3
357783

0.15961
cg09492169
ARHGAP27; ARHGAP27
181962

0.15953
cg27458177

478888

0.1592
cg03303857
GRIK4
66884

0.15887
cg11845549

221989

0.15871
cg15246712
EBF2
282686

0.15867
cg08009487
KRT4; KRT4
155576

0.15857
cg21429516

381785

0.15832
cg13552867
KCNJ9
250134

0.15799
cg22044408

391096

0.1579
cg13440947
GFRA1; GFRA1; GFRA1
247730

0.15763
cg14363469

266959

0.15736
cg08005872

155513

0.1573
cg00094585

2207

0.15729
cg04944536

98671

0.15686
cg04658243
RPTOR; RPTOR
93139

0.15641
cg11454459

215415

0.15627
cg11084571
KANK4
209299

0.15582
cg26227310
TLX1NB
457602

0.15574
cg05541311

109868

0.15565
cg00095431

2233

0.15534
cg08548284

165445

0.15493
cg03919650
MEFV
78874

0.15488
cg05786009

114191

0.15461
cg04024827
FLJ12825
80948

0.15448
cg15653254

289035

0.1544
cg04649598
ODZ4
92979

0.15426
cg08615354

166583

0.15398
cg05909702

116481

0.15394
cg08785724

169563

0.15382
cg00990769
MATN2; MATN2
20836

0.15381
cg08734931
FRMD4A
168749

0.15277
cg05277096
PDZRN3
104972

0.15274
cg25169706
ST5; ST5; ST5
A441040

0.15273
cg24572745
BOC
431168

0.15262
cg21176130
HLA-E
378075

0.15251
cg00514353
PCDH1
10956

0.15225
cg25515269
ITGA4
446437

0.15211
cg25653204
FPR2
448621

0.15196
cg25349820

443748

0.15173
cg11401293
COL6A1
214569

0.15074
cg14036069
NEK6; NEK6; NEK6; NEK6
260162

0.15059
cg14110685

261719

0.15038
cg11673092
ARMC3
218848

0.15033
cg24098326
TACC2; TACC2; TACC2; TACC2
423638

0.15015
cg17783086
LOC146880; LOC146880
324191

0.14948
cg17332379
LOC146880; LOC146880
317320

0.14904
cg26697605

465886

0.1489
cg16637224

305900

0.14883
cg19793499
AUTS2; AUTS2
356717

0.14862
cg13698865
COL5A1
253254

0.14823
cg14955976

277886

0.1482
cg24537942
KANK4
430673

0.14803
cg22958076

404890

0.14799
cg02079741
POMC; POMC
42708

0.14778
cg12055422

225496

0.14773
cg13947999

258288

0.1477
cg13121428
TGFB3
242270

0.14752
cg25651608

448592

0.14738
cg03573945
EBF2
72279

0.14713
cg07922154
ARG2
154039

0.14713
cg06516502

127100

0.14685
cg26719062

466225

0.14673
cg00020474

497

0.14661
cg07015554

137042

0.1466
cg02095937
TRIM59
43034

0.14648
cg22111167
PTPRJ; PTPRJ
392026

0.14639
cg16892553
PRR15L; PRR15L
310202

0.14634
cg00512602
SH3D20
10920

0.14595
cg27359636

477238

0.14577
cg23325335

411144

0.14539
cg15671996
TRIM15
289301

0.14536
cg14725580
C6orf106; C6orf106
274100

0.14511
cg13724550
FGF1; FGF1; FGF1; FGF1; FGF1;
253793

FGF1; FGF1

0.14497
cg19399514
RFTN1
349989

0.14495
cg11790417

220854

0.14482
cg15152115

281271

0.1445
cg11474182
CNTNAP3
215691

0.14435
cg05123976

101999

0.1441
cg03009240
FZR1
61309

0.14404
cg09359810
FRMD6
179634

0.14388
cg23931919

420690

0.14388
cg10321236
MYO7A; MYO7A; MYO7A
196418

0.1436
cg11222217
CASZ1; CASZ1
211555

0.14337
cg21487363
FOXP1; FOXP1
382660

0.14296
cg23522194
PLA2G4C; PLA2G4C; PLA2G4C
414285

0.14295
cg26871180

468843

0.14284
cg16139517
CNTN4
297000

0.14275
cg15371815
CRIM1
284394

0.14258
cg24118856
PPAN-P2RY11; P2RY11
423968

0.14258
cg15400997
PLXNC1
284893

0.14257
cg26950531
DPF1; DPF1; DPF1
470304

0.14252
cg23270841
PARD3B; PARD3B; PARD3B
410288

0.1418
cg00542975
CLASP1; CLASP1; CLASP1
11524

0.14168
cg06644998

129612

0.14118
cg04567302
SLC44A4
91475

0.14106
cg26002568

453787

0.14087
cg04289208
LGR6; LGR6
86168

0.14072
cg13085980
PLXNC1
241773

0.14055
cg18124852

329967

0.14042
cg13214162

243716

0.14037
cg07103748

138784

0.14016
cg04756252
SLA; SLA; TG; SLA
94952

0.13944
cg17253459
OLFML3
315956

0.1392
cg04601228
AUTS2; AUTS2
92149

0.13894
cg10005270
C10orf90
190712

0.13871
cg13948956

258313

0.1387
cg01211852

25460

0.13832
cg01654566

34124

0.13826
cg09528501

182620

0.13793
cg21688152
B3GNTL1
385901

0.13778
cg25472296
DOCK1
445774

0.13777
cg21951457
TACC2; TACC2; TACC2; TACC2
389827

0.13769
cg08102611
GAS7
157232

0.13766
cg13008631
IRS1
240565

0.13745
cg20535425

368163

0.13721
cg04689880

93734

0.13713
cg04768479

95139

0.13705
cg20438277
CD93
366734

0.13663
cg10301879
C6orf105; C6orf105
196052

0.13653
cg19582200
SCUBE1
352974

0.13647
cg25967170

453238

0.13638
cg06620993
SH3PXD2A
129075

0.13588
cg12812165
NIN; NIN; NIN
237654

0.13581
cg13053992

241251

0.13547
cg14598213
NGFR
271799

0.13528
cg19193956

346894

0.13503
cg06021990
FLT1
118695

0.13498
cg01715025
RNF115
35160

0.13498
cg05787209
STX1B
114223

0.13486
cg14206273
CASZ1; CASZ1
263709

0.13472
cg25599473
SMOC2; SMOC2
447739

0.13467
cg23200466
FBXW11; FBXW11; FBXW11
408900

0.13452
cg09868780
LVRN
188458

0.13444
cg05246303
ITGA4
104393

0.13439
cg03213259
TRADD
65187

0.13426
cg07067982
SLC43A3; SLC43A3; SLC43A3;
138080

SLC43A3

0.13383
cg24960118
PKHD1; PKHD1
437734

0.13373
cg06942124

135615

0.13373
cg06443678

125849

0.13342
cg18674487

338954

0.13337
cg11268280

212378

0.13318
cg08681473
COL1A1
167753

0.13306
cg03143046

63849

0.13304
cg06842253

133582

0.13286
cg26363935
NWD1
460109

0.13282
cg24250588
CLDN19; CLDN19
426051

0.13272
cg01579600

32722

0.13255
cg20567368

368674

0.13204
cg20054157
SFTA1P
361020

0.13169
cg16052198
FPR2
295658

0.13115
cg12888521

238770

0.13102
cg21322248
PSTPIP1
380448

0.13082
cg23418965
PKNOX2
412666

0.13073
cg10193441
HRNBP3
194174

0.13072
cg25566312
TGFBI
447171

0.13053
cg00334821
LIMK1
7073

0.13046
cg18132405
LEPREL1; LEPREL1
330109

0.13036
cg13893782
PDE7B
257077

0.13034
cg12575928
GAS2
233842

0.13018
cg03669949
DDX43; DDX43
74206

0.13012
cg19528338
BMP2
352128

0.13001
cg15878619
TUBB
292734

0.1298
cg07187808
KCNJ9
140601

0.1297
cg06641357

129537

0.12946
cg06618298
MYO10
129012

0.12929
cg04332927

87001

0.12922
cg11041060
SMOC2; SMOC2
208580

0.12875
cg19264571
APCDD1
347991

0.12861
cg00832547
RAGE
17556

0.12794
cg05376469

106960

0.1279
cg10331500
TGFA; TGFA
196606

0.12762
cg06983052
LRRC8D; LRRC8D
136433

0.12762
cg12019475

224847

0.12739
cg16900264

310326

0.12733
cg01055696

22251

0.12706
cg00652846
BOC
13828

0.12699
cg17265419
ITGA4
316124

0.12692
cg07570498
PHC2; PHC2
147621

0.12659
cg17504145
CRYBB2
320177

0.12646
cg00872354

18374

0.12628
cg08504407
HRNBP3
164658

0.12625
cg19072083

345194

0.12581
cg22660447
C16orf7
399970

0.12507
cg18169095
LAD1
330752

0.12494
cg24167667

424904

0.12488
cg02281167
TRIM15
46550

0.12477
cg18771659
SPRR1B
340554

0.12456
cg13197521
SPSB1
243430

0.12441
cg23733123
MARVELD1; MARVELD1
417794

0.12439
cg19681793
THBS2
354639

0.12435
cg22373687

395848

0.12435
cg01838728

37759

0.12422
cg03083517
COL22A1
62783

0.12417
cg01149239
MFI2; MFI2
24207

0.12417
cg05593669

110779

0.12379
cg00348891

7377

0.12362
cg19125999
C1orf172
345998

0.12359
cg26221801
C20orf195
457494

0.12334
cg01325188
BANP; BANP
27654

0.12301
cg08066024
NRXN1; NRXN1
156540

0.12289
cg04344730
DAB1
87247

0.12282
cg03467555

70136

0.12254
cg22124564
AMZ1
392246

0.12211
cg09882901

188677

0.1218
cg26472922

461941

0.12177
cg22810790
CA4
402441

0.1217
cg20396299

366115

0.1215
cg01399485
CASZ1; CASZ1
29081

0.12144
cg27423739

478314

0.12144
cg11857093

222224

0.12129
cg04004513
SKAP1; SKAP1
80529

0.12105
cg16731157
RCAN3
307717

0.12064
cg04757806
FUT4
94983

0.12052
cg10930901

206696

0.12044
cg09728333

185957

0.12032
cg22159835
NRXN2; NRXN2; NRXN2
392801

0.12007
cg10168635
C2orf88; C2orf88; C2orf88; C2orf88
193705

0.1198
cg12891678

238813

0.11957
cg06382546
LRP1B
124829

0.11923
cg16118803
MOG; MOG; MOG; MOG; MOG;
296688

MOG; MOG; MOG; MOG; MOG;

MOG

0.11879
cg24642523
HSPA2
432315

0.11842
cg05280131
FAM128A; LOC150776
105029

0.11823
cg23693749

417137

0.11821
cg25255713
EVPLL
442316

0.11814
cg23257225
ADORA1; ADORA1
410054

0.11813
cg12536891
CLPB
233264

0.11771
cg08922201
SYT7
172124

0.11744
cg16274954
DPCR1
299319

0.11728
cg04011829
SLCO4A1
80684

0.11703
cg16143578
ROBO4; ROBO4
297069

0.11698
cg09966895
ODZ4
190045

0.11691
cg24113950

423878

0.11646
cg19119609

345922

0.11612
cg05663064
COL6A1
112083

0.1161
cg19388972

349838

0.11582
cg05979400
LOC100128731
117903

0.11568
cg01311341
KIAA1671
27416

0.11546
cg06825512
APCDD1
133201

0.11466
cg26292150
ZDHHC19
458748

0.1146
cg06282247

123104

0.11404
cg17438457

319053

0.11398
cg06427611
PARVB
125571

0.11372
cg11386098
SYT7
214308

0.11358
cg13188382

243299

0.11315
cg03409151
ALDH7A1
68983

0.11311
cg18771300
RHOJ
340543

0.11298
cg15320349

283665

0.11293
cg03840259
GRAP2
77400

0.11242
cg03779072

76349

0.11235
cg00795584

16819

0.11176
cg06938705

135549

0.11144
cg04263215
NDUFS2; ADAMTS4
85649

0.11144
cg09296742

178512

0.11107
cg18804920
CNTNAP2
341118

0.11103
cg12835313
CACNA2D3
237974

0.11083
cg07157030
RHOJ; RHOJ
139948

0.11062
cg19725553
BLVRA
355438

0.11045
cg13777287
CNKSR3
254763

0.11016
cg26048630
PRRX1; PRRX1
454529

0.10972
cg02666837

54361

0.10966
cg11073796

209086

0.10936
cg04554928
TRIM15
91220

0.10888
cg17963461

327141

0.1087
cg15580417
KCNJ9
287721

0.10863
cg21602520
BCL2; BCL2
384588

0.10849
cg21817750
MRPS27
387694

0.10849
cg21306949

380293

0.10796
cg09126995
PHC2; PHC2
175501

0.10783
cg23931734
CA12; CA12
420686

0.10741
cg03679504
LRRC2; LRRC2; TDGF1
74369

0.10704
cg05272790
TMPRSS13
104903

0.10702
cg10512203
COL9A2
199691

0.10677
cg17848515
SMPD4; SMPD4; SMPD4; SMPD4;
325326

SMPD4; SMPD4; SMPD4;

FAM128B

0.10643
cg06824523
PLCH2
133178

0.10623
cg24833464
KRTAP3-1
435563

0.1062
cg01619846
UHRF1; UHRF1
33506

0.10589
cg00089821

2084

0.1058
cg02506908
HPD
51094

0.10525
cg24248680
FAM24B
426016

0.10495
cg22261895
PLBD1
394295

0.10453
cg25638443
ST8SIA1
448399

0.10437
cg08770647
ROBO4
169334

0.10378
cg10663897

202375

0.10325
cg09075327
PSD3
174665

0.10321
cg11505113
VASH2; VASH2; VASH2
216106

0.10291
cg24251135
USP38
426061

0.1029
cg26824174
OLFML3
467994

0.10284
cg11912513

223148

0.10264
cg03887520

78268

0.1024
cg21674153
B4GALT6
385733

0.10236
cg17147466

314205

0.10181
cg21931864
SH3D20
389527

0.10134
cg09469870

181594

0.10132
cg06294384

123314

0.10127
cg22693493

400543

0.10127
cg05492433
COL22A1
108970

0.10066
cg06915112

135102

0.10002
cg14320626

266136

TABLE 7

SEQ

OA − RA
Locus
Associated gene
ID No.

−0.10022
cg00490976

10388

−0.10038
cg00082140

1884

−0.10076
cg04080530

81955

−0.10083
cg25035059
CHD7
438996

−0.10092
cg09944434

189753

−0.10117
cg14538532
PBX2
270543

−0.10144
cg27165033

473953

−0.10204
cg03110300
CPLX4
63236

−0.10239
cg14729148
CUGBP2; CUGBP2; CUGBP2;
274152

CUGBP2

−0.10249
cg15730121
DLGAP4; DLGAP4; DLGAP4
290375

−0.10256
cg24037389
SCARA5
422606

−0.10268
cg20933239

374167

−0.10274
cg10627737
COL4A2
201776

−0.1028
cg19006947
PLCB3
344239

−0.10299
cg08613239

166546

−0.10305
cg15645757
UBE2Q1
288883

−0.10316
cg19056664
CLPTM1L
345033

−0.10356
cg03741475

75606

−0.10398
cg26332797
CTTNBP2
459481

−0.10398
cg07447015
ANKRD11
145230

−0.10414
cg06823060
CMIP; CMIP
133147

−0.10436
cg05150973
EHD1
102541

−0.10453
cg05587232
C7orf50; C7orf50; C7orf50
110657

−0.10463
cg26949393
AGAP3
470288

−0.10493
cg07266910
ZMAT3; ZMAT3
142085

−0.10509
cg01993576
SLC29A1; SLC29A1
40885

−0.10514
cg22907277
C7orf50; C7orf50; C7orf50
404094

−0.10515
cg12544243
GRIN3B
233359

−0.10541
cg23078123
GPR177
407010

−0.10541
cg09545918
COL8A1; MIR548G; COL8A1
182887

−0.1056
cg15067032

279802

−0.10586
cg24781973
FMN1
434762

−0.1059
cg07576033
C16orf11
147740

−0.10596
cg02256384

46036

−0.10602
cg08371643
CA4
162329

−0.10751
cg10985158
NAV1
207637

−0.10791
cg06531624

127430

−0.10813
cg25570929
COLEC12
447236

−0.1085
cg00997264

20997

−0.10866
cg18494399
SLC1A2
336159

−0.10876
cg21406461
IFI16
381503

−0.10879
cg24395452
SPATA18
428258

−0.109
cg10903916
ASAP2; ASAP2
206293

−0.1093
cg06330375
TSC2; TSC2; TSC2
123883

−0.10957
cg00779797
CAPN2; CAPN2
16482

−0.11024
cg18145505
GREM1
330327

−0.11042
cg26883033

469090

−0.11044
cg25334834
VGLL4; VGLL4; VGLL4; VGLL4
443491

−0.11048
cg18565130
C7orf50; C7orf50; C7orf50
337296

−0.11085
cg06067955
MYPN
119469

−0.11124
cg11147154
FLNC; FLNC
210249

−0.11125
cg14473823

269143

−0.11142
cg18324583

333319

−0.11152
cg24917359
C1QTNF1; C1QTNF1; C1QTNF1
437035

−0.11155
cg22346073
CLASP1; CLASP1; CLASP1
395428

−0.1116
cg04958191
ASPH; ASPH; ASPH; ASPH;
98926

ASPH

−0.11187
cg12160741
BRF1
227383

−0.11193
cg01821635

37390

−0.11205
cg03131767
ABCB9; ABCB9; ABCB9
63648

−0.11209
cg26576937
EBF4
463815

−0.11214
cg15142477
RNF165
281126

−0.1125
cg13893427

257066

−0.11262
cg17527422
C12orf68; C12orf68
320633

−0.1128
cg08642731
C10orf71; C10orf71
167107

−0.11281
cg15006627
GPRC5A
278771

−0.11292
cg12626411
PRG4; PRG4; PRG4; MIR548F1;
234784

PRG4

−0.1131
cg22851557
PRDM16; PRDM16
403103

−0.11319
cg26803803
DNMT3A; DNMT3A; MIR1301;
467585

DNMT3A

−0.11355
cg18746826
SCARA5
340084

−0.11368
cg26186331
DAB2
456925

−0.11378
cg15696968
KIAA1949; NRM; KIAA1949
289755

−0.11389
cg11014810
SH3PXD2A
208137

−0.11393
cg14190889
HLA-H
263376

−0.11407
cg17655346
CACNA2D3
322379

−0.11414
cg24777564
ADAMTS12
434703

−0.11439
cg04156383
PDE4DIP; PDE4DIP; PDE4DIP;
83534

PDE4DIP

−0.11448
cg02296376
MIR1286; RTN4R
46872

−0.11454
cg00145875

3263

−0.11464
cg21862126

388401

−0.11468
cg12181407

227738

−0.11476
cg21733013
RAPGEF5
386423

−0.11485
cg25379549
ADARB2
444296

−0.11508
cg07815521
MIR641; AKT2
152123

−0.11512
cg03037030
TNF
61825

−0.11515
cg14930864
YWHAQ
277519

−0.11516
cg23980760
ACCSL; ACCSL
421559

−0.11517
cg26858414
CDSN; PSORS1C1
468630

−0.11524
cg10831642
SH3PXD2A
205142

−0.11537
cg03901836
C2orf57
78575

−0.11539
cg16705287
POLR2E
307214

−0.11541
cg05557262
FAM180A
110128

−0.11544
cg03860038

77780

−0.11546
cg20989591
C7orf50; C7orf50; C7orf50
375141

−0.1157
cg03627771
GRAMD1B
73371

−0.1158
cg02145701
BANP; BANP
43968

−0.11616
cg13093380
ALK
241873

−0.11621
cg10239022
GPR133
195020

−0.1167
cg17753942

323769

−0.11676
cg21540399
PTPRG
383531

−0.11688
cg16538359

304039

−0.11692
cg01320211
SEMA6D; SEMA6D; SEMA6D;
27561

SEMA6D; SEMA6D; SEMA6D

−0.11693
cg02020821
PPP2R5C; PPP2R5C; PPP2R5C;
41450

PPP2R5C; PPP2R5C

−0.11698
cg06873401
LHFPL2
134232

−0.11705
cg15671083
UCN3
289292

−0.1173
cg00102093

2393

−0.11732
cg21356710
MFSD2B
380867

−0.11738
cg21205282

378649

−0.11761
cg07723948
OSGIN1; OSGIN1; OSGIN1
150463

−0.1177
cg16500916

303286

−0.11772
cg24634422
SLC1A2
432160

−0.11788
cg06755262

131696

−0.11803
cg24698488
MMP14
433309

−0.11805
cg01675953
MCF2L; MCF2L
34463

−0.11814
cg15547672
RPTOR; RPTOR
287142

−0.11827
cg23850174

419365

−0.1184
cg05429527

107954

−0.11845
cg27437823
MAP3K14
478553

−0.11865
cg15470365
SORBS2; SORBS2; SORBS2;
286032

SORBS2; SORBS2

−0.1187
cg24577455
PRKCZ; PRKCZ; PRKCZ
431245

−0.11873
cg18458739
BCAS3; BCAS3
335553

−0.11874
cg11335264
CAPZB
213463

−0.11901
cg00961940
TIMP2
20220

−0.11901
cg04712892
NRAP; NRAP
94119

−0.11917
cg27582168
FANCA
481016

−0.11931
cg17294136
CACNA2D1
316631

−0.11937
cg13932122

257954

−0.11937
cg10637688

201971

−0.11938
cg05384139
PITPNM2
107123

−0.11954
cg04554240
ESYT3
91205

−0.11954
cg22429169
ZNF335
396572

−0.11965
cg03917297

78835

−0.11967
cg19408740
IGSF8
350178

−0.11986
cg09745791
CTRB1
186257

−0.12011
cg06521562
JRK; JRK
127195

−0.12013
cg19678029
KCNQ1OT1; KCNQ1; KCNQ1
354576

−0.12018
cg09915421

189251

−0.12024
cg15827092

291857

−0.12026
cg25827666
SH2D2A; SH2D2A; NTRK1;
451242

NTRK1; SH2D2A; SH2D2A;

SH2D2A

−0.12033
cg14166209

262818

−0.12033
cg06647382
PDK2
129663

−0.12099
cg13543096
LOC100271831; GDPD3
249930

−0.12099
cg06679262

130241

−0.12103
cg05514932
RETSAT
109417

−0.12105
cg22624391

399439

−0.12109
cg19480385

351330

−0.12113
cg08325842
ZFP91; ZFP91-CNTF
161555

−0.12122
cg15368872
KLRK1
284353

−0.12175
cg27313492
WFIKKN1
476470

−0.12203
cg05182583
BAT2
103165

−0.12205
cg22193013
CHRNA7
393284

−0.12211
cg16209444
ACOX2
298173

−0.12214
cg20577102

368824

−0.12217
cg06326425
GPC6
123816

−0.1226
cg24353272
RRP15
427604

−0.12271
cg06306791

123517

−0.12281
cg11253913
CALD1; CALD1; CALD1;
212154

CALD1; CALD1

−0.12285
cg08352422

161993

−0.12293
cg16044109
HEG1
295491

−0.12298
cg23198815

408873

−0.12305
cg23922753

420530

−0.12305
cg15442583
CDGAP
285507

−0.12317
cg02248749
TNXB
45883

−0.12323
cg13455257
TMOD4
248067

−0.12337
cg00740389
ITGB7
15652

−0.12369
cg08448751
SEMA3G
163578

−0.1237
cg20663448
FILIP1
370104

−0.12374
cg00819141

17296

−0.12375
cg00161791

3633

−0.12376
cg01569083
TNF
32491

−0.12392
cg00254017
MAP3K1
5441

−0.12398
cg24885556
ITGA7
436558

−0.12399
cg21082141
PRDM8
376504

−0.12415
cg01785514
TATDN3; TATDN3; TATDN3;
36554

TATDN3; TATDN3

−0.12442
cg14771877
C17orf99
274788

−0.12455
cg02866149
C20orf117
58258

−0.12464
cg02667577
WIPI2; WIPI2; WIPI2; WIPI2;
54375

WIPI2

−0.12507
cg19973338
C17orf99
359782

−0.12517
cg13709561
SCARA5
253479

−0.12585
cg14118850
HPCAL1; HPCAL1
261879

−0.1259
cg03728674

75338

−0.12611
cg25340361
COMMD1
443580

−0.12613
cg07347019

143506

−0.12631
cg16000393
TNK2; TNK2
294736

−0.12649
cg02898239

58930

−0.12655
cg16323245
ZBTB20; ZBTB20
300173

−0.12655
cg00907661
ZDHHC20
19059

−0.12665
cg23986495

421674

−0.12691
cg13720395
YWHAG
253710

−0.12696
cg00643876
TBC1D24
13650

−0.12697
cg14781826
BPTF; BPTF
275014

−0.12748
cg01476807
FBXO30
30709

−0.1277
cg19659642
CD9
354321

−0.12785
cg21455901
CRYL1
382161

−0.1279
cg01876531
PLXNA2
38448

−0.12817
cg03925072

78966

−0.12858
cg24267275

426255

−0.12861
cg10356210
KCNK3
197004

−0.1289
cg12145349
NAA40
227108

−0.12904
cg11820824
S100A16
221475

−0.12906
cg26989053
NTAN1
471015

−0.12914
cg09119494
E2F2
175337

−0.12918
cg18904855

342756

−0.12918
cg00572560

12164

−0.12919
cg25242423
RTBDN; RTBDN
442118

−0.12926
cg26745520
GRK5
466632

−0.12934
cg07044523
S100A5
137607

−0.12938
cg10048215
APOLD1; APOLD1
191451

−0.12949
cg10471743

198906

−0.12978
cg00767886
EHD4
16225

−0.12983
cg26562772
DUSP10; DUSP10; DUSP10
463554

−0.13012
cg00877958

18503

−0.13016
cg21230535
FTCD
379161

−0.13031
cg09664445
KIAA0664
184948

−0.13045
cg06708731
DBH
130785

−0.13094
cg11585805

217365

−0.13101
cg10626556
KIAA0406
201746

−0.13101
cg09982224
ALDH3B1
190313

−0.13118
cg09437523

181003

−0.13123
cg06769258
MFSD7
132014

−0.13123
cg05299140

105372

−0.1315
cg25735648

449823

−0.13164
cg20865778
TCIRG1; TCIRG1
373291

−0.13179
cg12450872

231834

−0.13196
cg00154554
RERE; RERE
3460

−0.1321
cg10006897
PCBP3; PCBP3
190741

−0.13211
cg14602234

271884

−0.13235
cg08917489
EYA4; EYA4; EYA4
172050

−0.13261
cg24088438
FERMT3; FERMT3; FERMT3;
423490

FERMT3

−0.13277
cg07325692

143137

−0.13288
cg08013109
ULK1
155629

−0.13289
cg09337391
ZMYND8; ZMYND8; ZMYND8
179281

−0.13298
cg12430302
SPSB1
231458

−0.13311
cg22912818
TMCO3
404171

−0.13319
cg08338281
WIBG
161768

−0.13321
cg10097651

192354

−0.13345
cg08122070
NADK
157631

−0.13393
cg10723746
SPPL2B; SPPL2B
203334

−0.13398
cg21656522

385493

−0.134
cg24598094
SLC30A1
431596

−0.13423
cg03466066

70093

−0.13424
cg19503826
EPN1; EPN1; EPN1
351690

−0.13442
cg18330041
YWHAH
333416

−0.13456
cg25707745

449371

−0.13486
cg09018904
ANO10
173744

−0.13517
cg07908868
PLXNA2
153755

−0.13522
cg01364674

28371

−0.13527
cg24995976
PEAR1
438225

−0.13549
cg17802464
SEC14L3
324476

−0.13562
cg23941016
TBC1D2B; TBC1D2B
420855

−0.13568
cg14504636
AP2A2
269745

−0.13571
cg17846466
MCOLN2
325303

−0.13574
cg16950726
NLGN2
311097

−0.13588
cg07466788
SLC16A3; SLC16A3; SLC16A3
145619

−0.13613
cg00767135
ODZ3
16210

−0.13616
cg01336162
TGFBR3
27842

−0.13632
cg05007126
SDCBP2
99869

−0.13637
cg12045511
EHD4
225319

−0.13667
cg18028470
PIGV
328228

−0.13671
cg15773893
DOCK10
291034

−0.13693
cg05652528
DNMT3A; DNMT3A; DNMT3A;
111855

MIR1301

−0.13703
cg19931529
UGP2; UGP2
359121

−0.1372
cg22488568
SLC9A1
397378

−0.13723
cg14904034
HPCAL1; HPCAL1
277047

−0.13747
cg27027230
ARID5B
471633

−0.1377
cg06607384
C14orf159; C14orf159; C14orf159;
128776

C14orf159; C14orf159

−0.13773
cg09766355
NPL
186590

−0.13778
cg17015522
C1QTNF1; C1QTNF1; C1QTNF1
312055

−0.13789
cg19494960
RPTOR; RPTOR
351529

−0.13793
cg07366462
ADCY5
143859

−0.138
cg04075247
LGALS12; LGALS12; LGALS12;
81844

LGALS12; LGALS12

−0.13801
cg01174811
PDE4D; PDE4D; PDE4D
24728

−0.13825
cg15536489
C7orf50; C7orf50; C7orf50
286952

−0.13832
cg00622170
C4orf10; NOP14
13248

−0.13853
cg08743794
KIAA1949; NRM; KIAA1949
168897

−0.13873
cg21370522
TNF
381016

−0.13878
cg06047674
FRMD4A
119120

−0.13896
cg12225794

228457

−0.13921
cg05905731

116408

−0.13924
cg03407594
MUC6
68950

−0.13938
cg26605914
SKI
464218

−0.1394
cg07359991
HSD3B7; HSD3B7; HSD3B7;
143753

SETD1A

−0.13946
cg14780449

274978

−0.13949
cg16843799
FLJ39653; FLJ39653
309488

−0.13957
cg26805263
TNFRSF19; TNFRSF19
467622

−0.13961
cg13460740
MGC16703; P2RX6; P2RX6
248181

−0.13977
cg05488681

108898

−0.13998
cg17810878
ANO6; ANO6; ANO6
324639

−0.14009
cg12416561
C4orf22
231221

−0.14014
cg03649589
CSGALNACT1; CSGALNACT1;
73790

CSGALNACT1

−0.14031
cg07877964
USP7
153196

−0.14044
cg17499955

320108

−0.14047
cg17407629
PAM; PAM; PAM; PAM
318547

−0.14048
cg04305228
MICAL3
86473

−0.14066
cg24499411
TNS3
429956

−0.14066
cg17125990

313833

−0.14069
cg16608018

305379

−0.14074
cg15053322
SEC14L3
279556

−0.14077
cg11263420
FCGRT; FCGRT
212295

−0.14081
cg11437140
TIMP2
215182

−0.14083
cg07328796

143190

−0.14111
cg00528616
ZNRF1
11235

−0.14116
cg13619044
C7orf41
251590

−0.14119
cg03277153

66388

−0.14128
cg22321646
LZTS1
395060

−0.14131
cg11462252
SLIT3
215511

−0.14143
cg02711975
SNTG2
55231

−0.14153
cg18890417
RHOBTB2; RHOBTB2;
342552

RHOBTB2

−0.14155
cg19704102

355015

−0.14158
cg01982724

40687

−0.14161
cg01506917
TRERF1
31222

−0.14162
cg13868106

256590

−0.14164
cg27121538
SV2B; SV2B
473253

−0.14179
cg18657389
EVPL
338738

−0.14191
cg07044115

137597

−0.14228
cg26775558
TCF7L2; TCF7L2; TCF7L2;
467042

TCF7L2; TCF7L2; TCF7L2

−0.14233
cg01860954

38147

−0.14249
cg23951190
CPNE4
421020

−0.14255
cg20721467
MYST4
371233

−0.14265
cg12138483
CLPP
227002

−0.14272
cg11478024
ANKS1A
215738

−0.14274
cg16289449
FERMT3; FERMT3; FERMT3;
299541

FERMT3

−0.14274
cg14050363

260484

−0.14285
cg03905247
NCOR2; NCOR2
78635

−0.14288
cg08993079
ADAM12; ADAM12
173319

−0.14309
cg16224727
FBRSL1
298403

−0.14309
cg06385449
FERMT3; FERMT3
124889

−0.1432
cg17594351
MYF6
321588

−0.14328
cg12464631

232068

−0.14333
cg04244932

85279

−0.14351
cg04955877
ZHX2
98883

−0.14362
cg07618453
KCNQ1; KCNQ1
148575

−0.14384
cg27121309
ACER3
473247

−0.14384
cg14807945
ZEB2; ZEB2
275475

−0.14392
cg04142988
PCSK6; PCSK6; PCSK6; PCSK6;
83265

PCSK6; PCSK6; PCSK6;

PCSK6

−0.14429
cg00925950
PSKH1
19464

−0.14432
cg21933359
KHDRBS3
389559

−0.14433
cg11287400
MITF; MITF; MITF
212678

−0.14465
cg00926267
MKL1
19470

−0.14468
cg16098340
MIR548C; RASSF3
296333

−0.14478
cg08630040

166875

−0.14489
cg25880242

451900

−0.145
cg09706277
CD276; CD276
185655

−0.14524
cg07062388
LMBRD1
137963

−0.14533
cg02470874
PPM1L
50305

−0.14552
cg00997251
ARHGAP26; ARHGAP26
20995

−0.1456
cg16996242
ZMYM4
311738

−0.14564
cg12316142
DPYSL3
229823

−0.14568
cg05624853
HSD3B7; HSD3B7; HSD3B7
111349

−0.14588
cg05433460
ARHGAP1; ZNF408
108004

−0.1463
cg01226417

25743

−0.14632
cg00063979

1516

−0.14661
cg00498804
ST5; ST5; ST5
10580

−0.14682
cg22132509
PPM1L
392374

−0.14711
cg22166248
NXPH2
392926

−0.14724
cg02563600
KIAA0182; KIAA0182
52166

−0.14756
cg12681001
TNF
235670

−0.14759
cg23590159
UBXN11; UBXN11; UBXN11
415243

−0.14761
cg21528927
SLC6A12; SLC6A12; SLC6A12
383331

−0.1477
cg02742775
C12orf34
55869

−0.14778
cg10273072
C21orf34
195585

−0.14801
cg22927076

404363

−0.14817
cg03070550
HTRA1
62547

−0.14858
cg18791929
MYH15
340884

−0.14861
cg05991539
C6orf25; C6orf25; C6orf25;
118154

C6orf25; C6orf25; C6orf25

−0.14869
cg02092181
DOT1L
42966

−0.1488
cg13798679

255238

−0.14883
cg17073306
MYL5; MYL5
312976

−0.1489
cg17015179
PPT1; PPT1
312048

−0.14935
cg01343936

27981

−0.14948
cg11258484

212233

−0.14951
cg13971140
LASS4
258695

−0.14961
cg07282201
TBC1D10C
142343

−0.14982
cg12424504
MACC1
231361

−0.14985
cg01312762
CCDC134
27446

−0.15027
cg09568355

183338

−0.15031
cg08800856
NRXN2; NRXN2
169806

−0.15034
cg23617530

415668

−0.15048
cg02076598
KIAA1671
42633

−0.15058
cg18375707
PLCB3
334103

−0.1507
cg15833565
ERI3
291986

−0.15079
cg04101009

82356

−0.15089
cg09302355
FERMT3; FERMT3
178600

−0.15093
cg06191091

121594

−0.1512
cg07812957

152057

−0.15121
cg11724147
HIBADH
219728

−0.15134
cg27402999
SLC9A9
477987

−0.15154
cg02814691
NPL
57253

−0.15199
cg03907570
PRKAR1B; PRKAR1B;
78679

PRKAR1B; PRKAR1B;

PRKAR1B; PRKAR1B

−0.15217
cg13166875
SEC14L3
242924

−0.15227
cg26048923
TRAPPC9; TRAPPC9
454532

−0.15243
cg12884495
WBP2; UNC13D
238717

−0.15272
cg23558764

414863

−0.15282
cg05648614
ARL8B
111782

−0.15283
cg07449758
C6orf25; C6orf25; C6orf25;
145282

C6orf25; C6orf25; C6orf25

−0.15287
cg19642408

354063

−0.15303
cg14831085
PCSK6; PCSK6; PCSK6; PCSK6;
275823

PCSK6; PCSK6; PCSK6;

PCSK6

−0.15304
cg01882991

38611

−0.15305
cg20848130
GJC2
373060

−0.15327
cg16032111
PPP2R1B; PPP2R1B
295322

−0.15331
cg12268531
HSP90B3P
229089

−0.15337
cg08287887
OR7E37P
160856

−0.15355
cg14526997
EHMT1; EHMT1
270270

−0.15364
cg06569229
FAT3
128143

−0.15382
cg26485376

462139

−0.15389
cg15513221

286669

−0.15389
cg08577912

165952

−0.15392
cg05778820
SLC9A1
114033

−0.15397
cg02222066
CYTH1; CYTH1
45356

−0.15413
cg02112681
C7orf50; C7orf50; C7orf50
43376

−0.15419
cg02913511
CNNM4
59256

−0.15421
cg25368116

444093

−0.15435
cg01357135
PPM1L
28229

−0.15439
cg26139338
KLF12
456089

−0.15451
cg19351617
SIGIRR; SIGIRR; SIGIRR
349235

−0.15453
cg22852065
SPATA18
403114

−0.15478
cg14455925

268761

−0.15478
cg00594561
DLX3
12719

−0.15482
cg26114961
C6orf25; C6orf25; C6orf25;
455644

C6orf25; C6orf25; C6orf25

−0.15511
cg09996076
HSD3B7; HSD3B7; HSD3B7;
190546

SETD1A

−0.15544
cg07821417
ARVCF
152230

−0.1557
cg23991482
LSM7
421773

−0.15611
cg00751386
CTNNA2; CTNNA2
15883

−0.15614
cg02316852
RPA1
47305

−0.15619
cg21350115
CALCRL; CALCRL
380795

−0.15672
cg12526091

233088

−0.1568
cg02481950
METTL9; IGSF6; METTL9
50548

−0.157
cg19019345
ST5
344432

−0.15712
cg13552337
NDOR1; NDOR1; NDOR1;
250119

NDOR1

−0.15733
cg19321263
TRIM26
348840

−0.15767
cg07506749

146418

−0.15773
cg26197679

457116

−0.15792
cg03680790
STX2; STX2
74392

−0.15802
cg05744888
EIF2C2; EIF2C2
113460

−0.1583
cg00433709
ZNRF1
9174

−0.15835
cg22856279

403194

−0.15845
cg15256491
FOXK1
282829

−0.15854
cg20171297
MYF6; MYF6
362835

−0.15858
cg11244402
FOXO1
211986

−0.15879
cg14510322

269863

−0.15902
cg24236839
KDM4B
425869

−0.15907
cg01353907
GPR133
28172

−0.15926
cg23935522
ZDHHC17
420759

−0.15938
cg01893068

38791

−0.15944
cg20432350
KCND3; KCND3
366636

−0.15948
cg07453773
ST5; ST5; ST5
145358

−0.15956
cg11370814

214057

−0.15957
cg07820423

152210

−0.15972
cg00550928
MGAT3; MGAT3
11698

−0.15977
cg16576811
NEDD4L; NEDD4L; NEDD4L;
304754

NEDD4L; NEDD4L; NEDD4L;

NEDD4L; NEDD4L; NEDD4L

−0.15996
cg03285617
NT5E
66533

−0.1605
cg08145262
FRS2; FRS2
158124

−0.16083
cg07791897

151636

−0.16096
cg13127591
KRTAP9-9; KRTAP9-8
242341

−0.1612
cg00029979

743

−0.1613
cg18702278
PDE6B; PDE6B; PDE6B
339372

−0.16132
cg25683744
NINJ2
449043

−0.16135
cg13675051
RNF19A; RNF19A
252709

−0.16155
cg20364025
GALNS
365624

−0.16174
cg22649800
OGDH; OGDH
399813

−0.16179
cg07692929
OLFML1
149840

−0.16208
cg02903929

59057

−0.16229
cg10447977
ADAMTS9
198519

−0.1623
cg05383524
MGRN1; MGRN1; MGRN1;
107108

MGRN1

−0.16237
cg25902666
CSNK1G2
452187

−0.16237
cg07662964
BRD1; LOC90834
149327

−0.16243
cg14299931
ARHGEF7; ARHGEF7;
265726

ARHGEF7; ARHGEF7;

ARHGEF7; ARHGEF7

−0.16257
cg02017814
NSMCE2
41390

−0.16265
cg01703196

34921

−0.16293
cg02119955
ITGBL1
43511

−0.16305
cg17987982

327555

−0.1631
cg02449461
ARRB1; ARRB1
49866

−0.16315
cg03928874
LY86
79027

−0.16339
cg07735586

150671

−0.1634
cg21089930
DTX4
376611

−0.16371
cg25105578

440013

−0.16389
cg04021454
TAF12; TAF12
80874

−0.16408
cg21126020
TRIM10; TRIM10
377162

−0.16417
cg27395226
SRPK2
477869

−0.16428
cg09141623
PRKG1; PRKG1
175757

−0.16437
cg16746362
C6orf25; C6orf25; C6orf25;
307984

C6orf25; C6orf25; C6orf25

−0.16464
cg03273420
SMCR7; SMCR7; SMCR7
66322

−0.16496
cg04221461
AKT3; AKT3
84805

−0.16524
cg13573761
C4orf23
250625

−0.1653
cg17807913

324584

−0.16531
cg19506253
CYTIP
351732

−0.16538
cg00895231

18812

−0.16547
cg00671823
GTF3C1
14204

−0.16584
cg23632029
OR10A5
415943

−0.16593
cg04345118
PAX8; PAX8; LOC654433;
87257

PAX8; PAX8; PAX8; LOC440839

−0.16595
cg09228831
GPRIN3
177227

−0.16609
cg05910124
TRAPPC9; TRAPPC9
116485

−0.16622
cg15124432
CDC34
280793

−0.16631
cg03199366

64930

−0.16651
cg21524538
SDCBP2
383268

−0.16652
cg22950982
MAPKAPK3
404771

−0.1666
cg26807536
LOC100271831; GDPD3
467662

−0.16661
cg16618389

305550

−0.16665
cg18347607

333691

−0.16674
cg24828746
ZBTB7A
435490

−0.16708
cg01386735
LMBRD1
28819

−0.16723
cg12214366
ANTXR2; ANTXR2
228267

−0.16727
cg04132452
PPM1L
83027

−0.1674
cg17923377
BRD1; LOC90834
326503

−0.1675
cg00659931
PCSK6; PCSK6; PCSK6; PCSK6;
13955

PCSK6; PCSK6; PCSK6;

PCSK6

−0.16751
cg01412400
RPTOR; RPTOR
29361

−0.16763
cg18507146
ZNF236
336390

−0.16773
cg17001765
PGBD2; PGBD2
311841

−0.16781
cg23683146

416923

−0.16815
cg22688687
C19orf42
400457

−0.16825
cg10969245
DAGLA
207350

−0.16826
cg15637527
ARHGAP1
288736

−0.16829
cg11903920
TCERG1L
223003

−0.1685
cg15268191

283001

−0.16862
cg03204322
SAMD13; SAMD13; SAMD13
65015

−0.16866
cg09906928
LHFPL2
189108

−0.1688
cg23808165

418718

−0.16903
cg15594550
ZNF696
287945

−0.16921
cg08462367

163870

−0.16922
cg07412186
ATXN1; ATXN1
144647

−0.16923
cg02988730
AMPD2; AMPD2; AMPD2
60882

−0.16929
cg20090290
AMBRA1
361565

−0.16937
cg25296103
ZEB2; ZEB2
442878

−0.1694
cg25124489
PRKCE
440332

−0.1695
cg07739478
C6orf25; C6orf25; C6orf25;
150742

C6orf25; C6orf25; C6orf25

−0.16956
cg10090414

192177

−0.16978
cg08937102
NADK
172382

−0.16999
cg10785394

204327

−0.17008
cg05425699
TNS3
107909

−0.1701
cg12987138

240257

−0.17028
cg04558553
UGT2B7
91298

−0.17028
cg21764632
WIPI2; WIPI2; WIPI2; WIPI2;
386908

WIPI2

−0.17032
cg01306151
C16orf7
27295

−0.17039
cg22718891

400997

−0.17042
cg21346154
TGFA; TGFA
380741

−0.17048
cg21241151

379374

−0.17049
cg25091527
COL4A1
439775

−0.17072
cg26581714
SPATA18
463898

−0.17077
cg04771838
COL4A2
95213

−0.17083
cg04988694
TBCD
99510

−0.17083
cg05697734

112662

−0.17096
cg25221919

441857

−0.17096
cg18071202
LOC100292680
328953

−0.17113
cg19184688

346756

−0.17114
cg13740185
C10orf105; CDH23
254087

−0.17123
cg05801329

114496

−0.17126
cg26576576
PTPN14
463811

−0.17157
cg14692453
ANKRD23
273553

−0.17158
cg10143416

193223

−0.17163
cg05856321

115416

−0.17167
cg00230120
LOC100292680
4919

−0.17176
cg24152251

424608

−0.17178
cg18030453
LARS2
328261

−0.17206
cg25749107

450067

−0.17211
cg26457569
KANK2; KANK2
461638

−0.17223
cg08890627
SEC14L1; SEC14L1; SEC14L1;
171586

SEC14L1; SEC14L1

−0.17237
cg22481643
C3orf26; FILIP1L; MIR548G;
397283

FILIP1L; FILIP1L

−0.17247
cg08791347
FRMD4A
169648

−0.17248
cg08656333

167353

−0.17277
cg14121740

261943

−0.17277
cg05514531
GBE1
109409

−0.17287
cg00045902
PWWP2B; PWWP2B
1131

−0.17294
cg20584712
BAT2
368914

−0.17333
cg09305096
GULP1
178661

−0.17333
cg09156542

176059

−0.17338
cg05660874
SPPL2B; SPPL2B
112045

−0.17344
cg01397912
C19orf51; TNNI3
29052

−0.17357
cg19164997
CAPN5
346507

−0.17408
cg26110562
AGAP1; AGAP1
455549

−0.17424
cg19583934
RASA3
352999

−0.17429
cg20319604
PPM1B; PPM1B; PPM1B;
364994

PPM1B; PPM1B

−0.17454
cg02955940
CORIN
60186

−0.17456
cg05426956
HTRA1
107922

−0.17468
cg00128100
KIAA1949; NRM; KIAA1949
2929

−0.17519
cg01786151

36566

−0.17536
cg20788482

372245

−0.17539
cg04724873
KIAA1751
94344

−0.17547
cg11473240
KRT31
215681

−0.17547
cg10539122
NAV1; MIR1231; NAV1
200240

−0.17549
cg02123534
ADAP1
43564

−0.17597
cg05776861
ARHGEF7; ARHGEF7;
113995

ARHGEF7; ARHGEF7;

ARHGEF7

−0.17599
cg01104590
CARS; CARS; CARS; CARS
23322

−0.17623
cg24888581
AGAP1; AGAP1
436607

−0.17625
cg18805457
TCERG1; TCERG1
341130

−0.17669
cg08189139

158940

−0.17672
cg17644903
ZDBF2
322224

−0.17677
cg20725334

371301

−0.1769
cg00851627

17937

−0.177
cg05891054
STAT5B
116105

−0.17702
cg13609694

251374

−0.17731
cg19482843
EIF2C2; EIF2C2
351362

−0.17753
cg19975759
B3GNTL1
359813

−0.17754
cg24864413
SLC22A1; SLC22A1
436118

−0.1776
cg10592521
MEX3D
201161

−0.17783
cg21548131
NLGN1
383703

−0.178
cg02971328
RAC1; RAC1
60519

−0.17804
cg04857881
ITFG1
96921

−0.17826
cg16653138
PRKCZ; PRKCZ; PRKCZ
306192

−0.17831
cg22146612

392580

−0.17849
cg17627813
PRDM10; PRDM10; PRDM10;
322003

PRDM10

−0.17863
cg24522085
LASS6
430348

−0.17898
cg02374207
MACROD1
48511

−0.17927
cg01286133
APP; APP; APP; APP; APP
26850

−0.17931
cg04644504
SENP8; MYO9A
92888

−0.17974
cg01923312
SLC22A3
39391

−0.1805
cg25541708

446789

−0.1806
cg15852553

292348

−0.18062
cg18722504
HBEGF
339716

−0.18072
cg20440552

366770

−0.18085
cg12979590
CUGBP1
240142

−0.18112
cg18664915
C7orf50; C7orf50; C7orf50
338829

−0.18131
cg18080303
LAMA4; LAMA4; LAMA4;
329086

LAMA4; LAMA4

−0.18135
cg12496975
RAPGEF3; RAPGEF3; RAPGEF3
232622

−0.18167
cg25677376

448951

−0.18198
cg06476926
TBCD
126410

−0.18258
cg16161418
KIAA1949; KIAA1949
297331

−0.18265
cg14661139
UBE2J2; UBE2J2;
273045

LOC100128842; UBE2J2;

UBE2J2

−0.18273
cg07930874
SLAIN1; SLAIN1
154214

−0.18302
cg13912858
SORT1
257507

−0.18327
cg06059810
RUFY3; RUFY3; RUFY3;
119317

RUFY3; RUFY3

−0.18359
cg01822532
LRP5
37414

−0.18366
cg05059607
PITPNC1; PITPNC1
100893

−0.18367
cg07547798
NSMCE2
147165

−0.18371
cg04761972

95031

−0.18382
cg15932980
STX2; STX2
293635

−0.18394
cg17425351

318837

−0.18398
cg09777237
ELN; ELN; ELN; ELN; ELN
186754

−0.18403
cg04068914
MTHFSD; MTHFSD; MTHFSD;
81718

MTHFSD; MTHFSD; MTHFSD;

MTHFSD; FLJ30679

−0.18411
cg07224918
ARHGEF10L; ARHGEF10L
141354

−0.1845
cg24269082
TBCD
426275

−0.18457
cg00646241
SHANK2
13697

−0.18467
cg24290996

426537

−0.18474
cg13690679

253081

−0.18479
cg18926409

343073

−0.18495
cg19589494

353114

−0.18496
cg12806353
PLA1A
237540

−0.1853
cg00237010
NINJ2
5072

−0.18559
cg04144521
MFSD6
83296

−0.18565
cg07833951

152463

−0.18583
cg04056576
PPM1L
81465

−0.18583
cg14837896
THBS4
275954

−0.18588
cg22330533
BRD1; LOC90834
395190

−0.18592
cg03659680
LYN; LYN
73997

−0.18618
cg06795960
ARL4D
132561

−0.1862
cg14679230
LIPE
273341

−0.18622
cg00873517
KHDRBS3
18398

−0.18626
cg13613044

251444

−0.18636
cg20021790
RPH3AL
360547

−0.1866
cg08279097
DCLRE1B
160695

−0.18672
cg13613439
PHYHD1; PHYHD1; PHYHD1;
251453

PHYHD1; PHYHD1

−0.18676
cg25331919
LIPG
443459

−0.18684
cg16046833
SNX7; SNX7
295544

−0.18685
cg02535674

51638

−0.18728
cg27554156
GSG1; GSG1; GSG1; GSG1
480508

−0.18728
cg24940885

437453

−0.1873
cg02360002

48201

−0.18738
cg04912273
SLC9A1
98039

−0.18751
cg18321354
CARD11
333265

−0.18756
cg10453419
PCSK6; PCSK6; PCSK6; PCSK6;
198614

PCSK6; PCSK6; PCSK6;

PCSK6

−0.18757
cg04833731
GDPD3; GDPD3; LOC100271831
96391

−0.18789
cg16872841
COL4A2
309904

−0.18796
cg08176694
PITPNM2
158725

−0.1881
cg08426898

163219

−0.18822
cg02813863
APOLD1; APOLD1
57236

−0.1885
cg02959282
NCK1
60268

−0.1885
cg11458974
HMOX1
215460

−0.18885
cg01156373
ERBB4; ERBB4
24354

−0.18902
cg08405910
NCK2; NCK2; NCK2
162877

−0.18904
cg06445944
PIK3R1; PIK3R1; PIK3R1
125887

−0.18909
cg19623595

353718

−0.18909
cg05145297
HIP1
102438

−0.18938
cg11626175
JARID2
218013

−0.18939
cg05310046
THSD4
105621

−0.18981
cg26005086
JAG1
453833

−0.18991
cg09990852
RUFY3; RUFY3; RUFY3;
190465

RUFY3; RUFY3

−0.19005
cg23413567
FOXO1
412578

−0.19014
cg11815008
CETN1
221367

−0.19024
cg14883993
NFIC; NFIC
276772

−0.1905
cg27302175
ZSWIM6
476195

−0.19064
cg05647929
CFC1B; CFC1
111770

−0.19077
cg00859622
VSTM2L
18096

−0.19081
cg25940447
GNPDA1
452774

−0.19085
cg00213052

4580

−0.19087
cg03057216
VPS72; TMOD4
62283

−0.19087
cg01932663
C3orf26; FILIP1L; FILIP1L
39583

−0.19118
cg25026329
APLP2; APLP2; APLP2; APLP2;
438829

APLP2; APLP2

−0.1912
cg06758827
TRIO
131795

−0.19133
cg09353563
UACA; UACA; UACA
179511

−0.19136
cg20629021
CPT1A; CPT1A
369542

−0.19145
cg07823562
CYTH1; CYTH1
152263

−0.19146
cg23429240
CORO1C
412803

−0.19147
cg03320743

67233

−0.19215
cg10407488
ARHGEF12
197843

−0.19222
cg19876649
MYOM1; MYOM1
358154

−0.19233
cg13148151
LIMD1
242630

−0.19234
cg24073770

423219

−0.19257
cg08010094
NXPH2
155586

−0.19262
cg01742357
RAPGEF4; RAPGEF4
35676

−0.19263
cg05957190
CHST11
117447

−0.19286
cg07394266
C9orf71
144374

−0.19326
cg00689612
TIMP2
14559

−0.19327
cg12131324
RPTOR; RPTOR
226898

−0.19329
cg07155381
RPH3AL
139908

−0.1934
cg13189271
JARID2
243319

−0.19379
cg03447908
CLEC3B
69735

−0.1938
cg19185706
LDB3; LDB3; LDB3
346776

−0.19452
cg12744888
MYH15
236621

−0.19464
cg04081835

81973

−0.1948
cg05297666
ETS1
105349

−0.19506
cg19252218
ARL4D
347770

−0.19508
cg11668573
FNIP2
218773

−0.19509
cg07879785
CRYL1
153222

−0.19518
cg04005958

80561

−0.19522
cg01617074
SLC45A4; SLC45A4
33454

−0.19532
cg12560421

233610

−0.19534
cg00498089

10560

−0.19543
cg17622952

321946

−0.1955
cg05541460

109873

−0.19558
cg02073224
MEGF6
42570

−0.19569
cg07983363
PCSK6; PCSK6; PCSK6; PCSK6;
155143

PCSK6; PCSK6; PCSK6;

PCSK6

−0.19582
cg00989315
CDCA7L; CDCA7L; CDCA7L
20808

−0.19585
cg11634496

218142

−0.19592
cg14887955

276836

−0.19603
cg10345724
C7orf50; C7orf50; C7orf50
196843

−0.1963
cg14002578
GALNT12
259402

−0.19635
cg02670123
ITGA6; ITGA6
54419

−0.19673
cg12056017
ANKRD44
225506

−0.19679
cg03462604
C2orf18
70013

−0.1968
cg02800733
CD320; CD320
57003

−0.19696
cg18835549
TRIM40
341642

−0.19701
cg08079387
LOC90834; BRD1
156793

−0.19706
cg22251117
RPH3AL
394137

−0.19709
cg02382878

48672

−0.1974
cg14710529
ASAP2; ASAP2
273872

−0.19767
cg01891925
BTC
38772

−0.19768
cg20439101
MAP3K1
366753

−0.19769
cg06709178
INPP5B
130792

−0.19814
cg07573020
ANKH
147681

−0.19821
cg08373573
MUC6
162363

−0.19832
cg27396760
CMIP; CMIP
477898

−0.19891
cg05796178
LZTS1
114384

−0.19909
cg25345520

443680

−0.19912
cg21562035
KANK2; KANK2
383932

−0.19945
cg06136573

120675

−0.19954
cg18756557
LOC100292680
340244

−0.19966
cg06049177
GSR
119151

−0.19972
cg24536145
SORBS2
430636

−0.19978
cg16875057
STK39
309942

−0.20006
cg01698392
TIMP2
34835

−0.2003
cg12251803
LRRFIP1; LRRFIP1; LRRFIP1;
228847

LRRFIP1; LRRFIP1

−0.20035
cg21007971
PLA2G6; BAIAP2L2; PLA2G6
375427

−0.20045
cg04142824
ATP11A; ATP11A
83262

−0.20048
cg00435616
C7orf50; C7orf50; C7orf50
9208

−0.20064
cg04094923

82221

−0.20076
cg13496793
ZBTB34
249014

−0.20101
cg23659250
BRD1; LOC90834
416462

−0.20138
cg15690822
RFFL; RFFL
289648

−0.2019
cg02019508
ATF7; ATF7; ATF7
41425

−0.20196
cg08577298

165938

−0.20213
cg25238480
GALNTL4
442087

−0.20221
cg12294678
NOS3
229476

−0.20232
cg21881338
AACS
388735

−0.2025
cg24901662
PARD3
436800

−0.20251
cg11407540
EGF
214668

−0.20269
cg07069839

138124

−0.20308
cg21931263

389515

−0.20316
cg11561301
C4orf6
216983

−0.20337
cg07795513
ATF6
151706

−0.20362
cg04589673

91937

−0.20374
cg06418113
RNF165
125411

−0.20385
cg01471802
TRIM6-
30616

TRIM34; TRIM6; TRIM6

−0.20416
cg15884713
NINJ2
292821

−0.2046
cg22043118
TMED7-
391069

TICAM2; TICAM2; TMED7-

TICAM2

−0.20502
cg07593326
PCCA; PCCA
148106

−0.20504
cg12800012
SH3PXD2A
237419

−0.20507
cg04667640
ZFHX3; ZFHX3
93314

−0.20511
cg00527307

11212

−0.2055
cg13300630
ROBO1; ROBO1; ROBO1;
245107

ROBO1

−0.20558
cg25888386

452027

−0.2057
cg03571277
ACCN1
72232

−0.20574
cg19660729
KIF26A
354335

−0.206
cg13689563
ZNF136
253055

−0.20627
cg27585074
CSNK1G2
481080

−0.20638
cg25266816

442457

−0.20669
cg15984712

294427

−0.2068
cg08124461
CGNL1
157691

−0.20692
cg12555652
ITGBL1
233545

−0.20701
cg06707286
PCSK6; PCSK6; PCSK6; PCSK6;
130749

PCSK6; PCSK6; PCSK6;

PCSK6

−0.20713
cg12758625
RNF24; RNF24; RNF24
236809

−0.20719
cg16241878
FRMD5
298677

−0.20733
cg06389019
SLC9A3R1
124935

−0.20737
cg02803847
BUB3; BUB3
57065

−0.20737
cg07376547

144035

−0.20746
cg20625588
MUC6
369496

−0.20756
cg05415840
ARC; ARC
107735

−0.2077
cg00311751
TRERF1
6568

−0.20775
cg02465887
DCHS2
50200

−0.20799
cg02392737
ADCY9
48895

−0.20804
cg13043815
C21orf63
241083

−0.20812
cg06232466
CACNA1H; CACNA1H
122343

−0.20827
cg08490246

164404

−0.20838
cg05964487

117593

−0.20854
cg15891850
KLF12
292938

−0.20874
cg20218678
FAM10A4
363445

−0.20882
cg01569709

32505

−0.20902
cg15044010
SRPK2; SRPK2
279419

−0.20915
cg10269431
EGF
195527

−0.20964
cg01064758
TG; SLA; SLA
22444

−0.21022
cg12597325
STX2; STX2
234249

−0.21045
cg20263733
ATP2C1; ATP2C1; ATP2C1;
364115

ATP2C1

−0.21084
cg02872914
CTBP2; CTBP2; CTBP2
58381

−0.21116
cg14153069
PHYHD1; PHYHD1; PHYHD1;
262529

PHYHD1; PHYHD1

−0.21127
cg21617357
HTATIP2; HTATIP2; HTATIP2;
384851

HTATIP2; HTATIP2

−0.2114
cg23723013
KCNAB1; KCNAB1; KCNAB1
417619

−0.21172
cg02497428
METTL9; IGSF6; METTL9
50892

−0.2118
cg12018521
TES
224833

−0.21202
cg02773403
ANK3
56524

−0.21204
cg00765737
COL4A2
16178

−0.21216
cg06432487

125644

−0.21225
cg13447820

247908

−0.21276
cg04470324
FSTL4
89614

−0.21292
cg26295272
FLNB; FLNB; FLNB; FLNB
458803

−0.21314
cg05450916
TGFBR2; TGFBR2
108229

−0.21317
cg04893454

97666

−0.21341
cg22219255

393632

−0.21349
cg23198558
ARHGAP26; ARHGAP26
408866

−0.21367
cg19353947
ZEB2; ZEB2; ZEB2
349264

−0.21373
cg04208996

84534

−0.2138
cg02534659

51624

−0.21385
cg04266607
JAZF1
85718

−0.21392
cg07042532
CREB5; CREB5; CREB5
137576

−0.21393
cg09130535
ADRBK1
175551

−0.21397
cg24919468

437059

−0.21428
cg00058644

1391

−0.2144
cg06127541
RRAS2; RRAS2
120526

−0.21446
cg16497661
CKB
303238

−0.21492
cg02712587
EIF2AK4
55252

−0.21494
cg00232092
FBXL18
4975

−0.21509
cg13679772
FOXN3
252820

−0.21555
cg01915822
ADCK5
39234

−0.21558
cg11460562
TNPO1; TNPO1
215482

−0.21561
cg14375985
CTBP2; CTBP2; CTBP2
267187

−0.21562
cg04267284
PYGB
85734

−0.21585
cg19093405
CACNA2D3
345515

−0.21621
cg02668218

54387

−0.21671
cg25286715

442752

−0.21697
cg14772660
SLC5A7
274806

−0.21707
cg01495332
GRB10; GRB10; GRB10
31016

−0.21758
cg00446697
HCCA2
9405

−0.21821
cg03844838
DIP2C
77475

−0.21834
cg25799348
FOXK1
450816

−0.21849
cg08702689
PRRX1; PRRX1
168159

−0.21863
cg13495373
CREB5; CREB5; CREB5
248982

−0.21887
cg11165960

210588

−0.21906
cg24721647
ACSL1
433758

−0.21922
cg15380511

284521

−0.21944
cg07739826
OSBP
150749

−0.21962
cg18780243
EEF1DP3
340687

−0.21966
cg13289202
ABTB2
244906

−0.21972
cg00684423
GPER; C7orf50; C7orf50; GPER;
14439

C7orf50

−0.21994
cg06013113
RAB40C
118547

−0.21999
cg18129282

330053

−0.22012
cg26325949
SYNPO2; SYNPO2; SYNPO2
459352

−0.22027
cg07091154
SHANK2
138518

−0.22031
cg27584112

481064

−0.22034
cg20203400
TMEM182
363230

−0.22065
cg14125542
FAM49A
262013

−0.22071
cg00380924
RPS6KA2; RPS6KA2
8060

−0.22081
cg18887296
PPFIA3
342507

−0.22107
cg17858500
C20orf27
325500

−0.22142
cg04974647

99207

−0.22165
cg20334115
PYCR2
365215

−0.22175
cg16523645
ITPK1; ITPK1; ITPK1
303721

−0.22212
cg12525096

233069

−0.22213
cg20131219
PHLDB2; PHLDB2; PHLDB2;
362199

PHLDB2

−0.22244
cg21750426
MIRLET7C; C21orf34; C21orf34;
386667

MIR99A

−0.22263
cg17918796

326430

−0.22269
cg14165772

262803

−0.22294
cg14081251
ST6GALNAC4; ST6GALNAC4
261114

−0.22318
cg01824625
EPHA3; EPHA3
37465

−0.22327
cg20080845
BRD1; LOC90834
361454

−0.2235
cg15016481
LRRFIP1; LRRFIP1; LRRFIP1;
278955

LRRFIP1; LRRFIP1

−0.22429
cg04112058
SHCBP1
82595

−0.22434
cg17879450
MACF1
325874

−0.2244
cg12399224
ZBTB46
230928

−0.22443
cg22909677
ARMC2
404123

−0.22448
cg25874123
MYOM1; MYOM1
451828

−0.22451
cg18720326
ADAMTS2; ADAMTS2
339675

−0.2246
cg16230121
APBB1; APBB1
298473

−0.22463
cg21848191
RAD51L1; RAD51L1; RAD51L1
388170

−0.22463
cg19026231
GALK1
344545

−0.22483
cg07080231

138324

−0.22528
cg17531430
BIN1; BIN1; BIN1; BIN1; BIN1;
320696

BIN1; BIN1; BIN1; BIN1; BIN1

−0.22531
cg07807373

151942

−0.22568
cg09038971
CHST11
174071

−0.22576
cg16624521

305662

−0.22583
cg10031769
CREM; CREM; CREM; CREM;
191189

CREM; CREM; CREM; CREM;

CREM; CREM; CREM;

CREM; CREM; CREM; CREM;

CREM; CREM; CREM;

CREM; CREM

−0.22674
cg15853771

292370

−0.22677
cg05242915

104329

−0.22727
cg09264140
FMNL1
177950

−0.22741
cg24977338
RGPD8; RGPD5
437964

−0.22749
cg27469810
CETN1
479043

−0.22788
cg00653025

13831

−0.22788
cg05285759
TBCK; TBCK; TBCK; TBCK
105125

−0.22818
cg12642431
UACA; UACA
235055

−0.22826
cg09169413
P11
176276

−0.22856
cg23079012

407020

−0.2289
cg23904501
PTPRS; PTPRS; PTPRS; PTPRS
420216

−0.22901
cg07631435
ZBTB16; ZBTB16
148813

−0.22976
cg13752933
DAPK1
254331

−0.22984
cg19173502
MIRLET7C; C21orf34; C21orf34
346603

−0.22995
cg21502482
SPATA7; SPATA7
382912

−0.22997
cg03144446

63874

−0.23001
cg01164141

24508

−0.23003
cg27314273
PTPRG
476489

−0.23018
cg13879937
EHD4
256817

−0.23035
cg11168687
ACSL1
210627

−0.23037
cg22905866

404070

−0.23047
cg19788250
APP; APP; APP; APP; APP
356630

−0.23055
cg19478371
PPP2R5C; PPP2R5C; PPP2R5C;
351294

PPP2R5C; PPP2R5C

−0.23081
cg08153404

158265

−0.23098
cg11945474

223676

−0.23103
cg07470830

145712

−0.23116
cg09537792
ANKRD11
182760

−0.23122
cg17880118
COL4A1
325886

−0.2315
cg07468585

145653

−0.23177
cg00108038
LOC100292680
2509

−0.23183
cg23560676
NSMCE2
414881

−0.23213
cg11063877
LARP4; LARP4; LARP4; LARP4;
208898

LARP4; LARP4; LARP4

−0.23228
cg19735406
COL4A2
355626

−0.23258
cg09259797

177870

−0.23286
cg05314142
SLC22A1; SLC22A1
105694

−0.23299
cg06519061
PTPN14
127144

−0.23315
cg26983411

470886

−0.23331
cg01417625
LAMC2; LAMC2
29483

−0.23345
cg06112923
STEAP2; STEAP2; STEAP2
120290

−0.23386
cg22416916
SLC22A1; SLC22A1
396454

−0.23403
cg10492417
FANCA
199244

−0.23409
cg02540833
SHANK2
51760

−0.2342
cg09329079
TMEM184A
179139

−0.23446
cg08135718
CUX1; CUX1; CUX1
157939

−0.23468
cg20724690
CAB39; CAB39; CAB39
371287

−0.23494
cg20192387
RPS6KA2; RPS6KA2
363087

−0.23519
cg09169739
GFPT2
176289

−0.23558
cg22396663
MAD1L1; MAD1L1; MAD1L1
396208

−0.23597
cg02923628

59493

−0.23632
cg03109660
RELL1; RELL1
63223

−0.23648
cg06562964
RELL1; RELL1
128035

−0.23857
cg17133045
AKT3; AKT3
313972

−0.23937
cg03606098
NADK
72963

−0.23938
cg18771195
RPH3AL
340542

−0.23963
cg10013121
TRERF1
190859

−0.23979
cg02781060

56673

−0.23996
cg22117968

392140

−0.2401
cg11520719
ARID1B; ARID1B; ARID1B
216320

−0.24011
cg04126956
TRAPPC9; TRAPPC9
82912

−0.24087
cg01312265
TCERG1L
27436

−0.24102
cg09873409
PLXNA4; PLXNA4
188543

−0.24159
cg00089451

2073

−0.24161
cg27446233
PFKM; PFKM; PFKM; PFKM;
478685

PFKM

−0.24161
cg07251141
ADAM12; ADAM12
141811

−0.24173
cg02773698
FCHSD2
56533

−0.2419
cg11028872

208387

−0.24214
cg06865642
BRD1; LOC90834
134034

−0.24269
cg18000216
ERC2
327710

−0.24279
cg14558716
ATF1
270966

−0.24303
cg06165742
FOXP2; FOXP2; FOXP2
121155

−0.24317
cg07491828
MKL2
146139

−0.24321
cg05495611
EXT2; EXT2
109044

−0.24432
cg00264129
HBEGF
5659

−0.24487
cg20539449

368227

−0.24494
cg07877629

153192

−0.24502
cg00026412
ANK3
645

−0.24505
cg25089903
NINJ2
439753

−0.24567
cg23708624
CCDC146; FGL2
417387

−0.24585
cg25838968
PLXNA2
451397

−0.24656
cg02724461
GALNS
55487

−0.24687
cg23669855
LYSMD4
416659

−0.24737
cg19547694
BRD1; LOC90834
352451

−0.24757
cg13962170

258544

−0.24861
cg17798857
UACA; UACA
324425

−0.24871
cg09741789
FBN1
186193

−0.24879
cg04721825
PRKCA
94264

−0.24908
cg01556677
SEMA3C
32186

−0.24945
cg19450056

350853

−0.24949
cg25141441
RORA; RORA; RORA; RORA
440625

−0.24973
cg04265492
BAI2
85697

−0.2506
cg03870329

77949

−0.25077
cg25206802
SACS
441606

−0.25093
cg25483191
TRIM55; TRIM55; TRIM55;
445943

TRIM55

−0.25124
cg08535361
NTN4
165209

−0.25143
cg04425710
ESCO2; CCDC25
88827

−0.25168
cg08464954

163934

−0.25182
cg13661832

252443

−0.25199
cg10259111
GNG2
195382

−0.25214
cg24331722

427189

−0.25249
cg26529437
ITGB8
462893

−0.25283
cg25706447
PIGV
449350

−0.25296
cg26131670
SLC4A4; SLC4A4
455944

−0.25313
cg11274148
RPTOR; RPTOR
212468

−0.25324
cg14571004
GALNT12
271226

−0.25333
cg26306638
HBEGF
459010

−0.25362
cg08412699
ITGB8
162975

−0.25409
cg12208381
CSNK1G2
228165

−0.25453
cg11611676

217803

−0.25457
cg13665060

252509

−0.25472
cg16784943
ITPK1; ITPK1; ITPK1
308597

−0.25501
cg24534767

430608

−0.25576
cg03778207
ME3; ME3; ME3
76334

−0.25579
cg09088836

174888

−0.25665
cg26543192

463160

−0.2568
cg14457429

268785

−0.25731
cg16834726
DCTN2
309390

−0.25741
cg14523881
VASH2; VASH2; VASH2
270202

−0.25788
cg05208056
NCK2; NCK2; NCK2
103597

−0.25817
cg07525751
SLC6A3
146753

−0.25823
cg03855388
CPT1A; CPT1A
77697

−0.25832
cg22308453
DPYSL2
394900

−0.25865
cg07911905
CHST11
153817

−0.25865
cg05196076
FBXO31; FBXO31
103393

−0.25949
cg18371976
TRERF1
334048

−0.25957
cg16878214
PLEKHF2
309991

−0.25958
cg20655877

369984

−0.26099
cg21197233
ARHGAP20
378484

−0.26155
cg15568998
AGMAT
287517

−0.26178
cg27511861

479747

−0.26219
cg12564175
ESCO2; CCDC25
233667

−0.26237
cg16090790

296212

−0.2632
cg12552626
CCDC146; FGL2
233502

−0.26416
cg11072779
ANXA4
209068

−0.26569
cg22352504
HAS1
395515

−0.26608
cg07263759

142020

−0.26615
cg18022344
METTL9; IGSF6; METTL9
328111

−0.2662
cg24033633

422524

−0.26675
cg05310185
TACC2; TACC2; TACC2; TACC2
105623

−0.26683
cg02606505
NKTR
53079

−0.26684
cg05899338
ZNF239; ZNF239; ZNF239
116275

−0.26725
cg06385757
PRKAR1B; PRKAR1B;
124893

PRKAR1B; PRKAR1B;

PRKAR1B; PRKAR1B

−0.26763
cg14178899
ERRFI1
263095

−0.2679
cg03372385
LRRC16A
68299

−0.26797
cg25072766
CARS; CARS; CARS; CARS
439518

−0.26865
cg20608783
BAI2
369275

−0.26917
cg07776993
ADCK5
151365

−0.27071
cg01295631

27066

−0.27154
cg06836480
DHRS9; DHRS9; DHRS9
133449

−0.27159
cg01957599
FAM13AOS
40119

−0.2728
cg17478992
SLC12A8
319759

−0.27286
cg12884466
MRPL3
238716

−0.27379
cg13200640

243476

−0.27391
cg12619262

234658

−0.27459
cg26551026
CABLES1; CABLES1
463331

−0.27512
cg03078520
MICAL3; MICAL3; MICAL3
62698

−0.27559
cg19295451
PCSK6; PCSK6; PCSK6; PCSK6;
348451

PCSK6; PCSK6; PCSK6;

PCSK6

−0.2759
cg01359165

28268

−0.27611
cg03389789
FBXW8; FBXW8
68597

−0.27642
cg27199697
DLX3
474550

−0.27828
cg19995595
ITPK1; ITPK1; ITPK1
360131

−0.2796
cg19600494

353349

−0.28011
cg22801134
PRICKLE2
402255

−0.28065
cg20140333

362329

−0.28088
cg00101350
MGAT3; MGAT3
2375

−0.28176
cg10784341
PHACTR2; PHACTR2
204295

−0.28206
cg23338380
CUX1; CUX1; CUX1
411370

−0.28216
cg22122925
ERRFI1
392216

−0.28241
cg06235645
SEMA6D; SEMA6D; SEMA6D;
122412

SEMA6D; SEMA6D; SEMA6D

−0.28268
cg16474725
CLIC5; CLIC5
302879

−0.28421
cg14054582

260566

−0.2851
cg19926144
DIP2C
359006

−0.28525
cg26214026
ATXN2
457353

−0.28725
cg18030133
PHACTR2; PHACTR2;
328254

PHACTR2; PHACTR2

−0.28771
cg22716599
DNM3; DNM3
400952

−0.28822
cg00745735
MYPN
15768

−0.28884
cg02071553
MIR216B
42524

−0.28893
cg01756899

35949

−0.28929
cg05928904

116850

−0.28962
cg01598421
TG
33081

−0.28997
cg02131142
TBC1D9B; TBC1D9B
43723

−0.29156
cg03412557
RUNDC2A
69042

−0.29166
cg17947992

326928

−0.29212
cg00855685
SEMA5A
18020

−0.29231
cg08672203
PPAP2A; PPAP2A
167602

−0.29315
cg17613911
STK32A
321844

−0.29506
cg23666374
AUTS2; AUTS2; AUTS2
416583

−0.29533
cg16666745
GALNT10
306478

−0.2964
cg26826631
CD55; CD55
468043

−0.29748
cg17919396
ALDH1A3
326446

−0.29758
cg01574912

32628

−0.29814
cg14334389
SPARCL1; SPARCL1
266428

−0.29818
cg04304338
ANKRD33B
86451

−0.29932
cg02847703
BTC
57849

−0.30181
cg23155767
GPR1; GPR1
408172

−0.30344
cg09819635
KHDRBS3
187501

−0.30363
cg25131079
ADAMTS2; ADAMTS2
440427

−0.30642
cg12754854
PHYHD1; PHYHD1
236759

−0.30675
cg08943696
GPR133
172510

−0.30689
cg03983715
PRMT7
80095

−0.30824
cg09287328

178354

−0.30861
cg03713317
CYFIP1; CYFIP1
74995

−0.31349
cg23666829
TBCD
416590

−0.31884
cg26253868

458047

−0.32034
cg03700279
PREPL; PREPL; PREPL; PREPL;
74742

PREPL; PREPL; PREPL

−0.32126
cg12894142

238844

−0.32278
cg16689609
UTRN
306875

−0.32343
cg12359895
LOC100216001; LOC338588
230357

−0.32409
cg19244380
AMBRA1; AMBRA1
347620

−0.32631
cg01928411
LARP4; LARP4; LARP4; LARP4;
39500

LARP4; LARP4; LARP4

−0.32706
cg25254949

442307

−0.32836
cg23159678
NOVA1; NOVA1; NOVA1
408237

−0.33031
cg11520439
LOC286367
216313

−0.33087
cg11937508
GPR1; GPR1
223523

−0.33212
cg12205433
TES; TES
228120

−0.33433
cg18901940
MYPN; MYPN
342719

−0.34043
cg10362527
GPR1; GPR1
197111

−0.34108
cg14570632
RXRA
271222

−0.34414
cg03361973
SEMA6D; SEMA6D; SEMA6D;
68105

SEMA6D; SEMA6D; SEMA6D

−0.34417
cg05073720
PHLPP1
101171

−0.34459
cg16087541
TES; TES
296173

−0.34847
cg09835421
PRMT7
187811

−0.34934
cg21161187
SLC6A3
377787

−0.35195
cg02666566

54356

−0.35418
cg18262591
CPT1A; CPT1A
332336

−0.37588
cg16808481
TES; TES
309027

−0.38211
cg14604584

271938

−0.40768
cg05110241
PRMT7
101782

−0.41512
cg20071744
TRAPPC9; TRAPPC9
361314

−0.43386
cg15853299
TBCD
292363

TABLE 8

Associated

OA − RA
gene
CpG*
Locus
SEQ ID No.

−0.603
LIMS1
2: 109251064
cg10879348
205889

−0.603

15:97311928
cg04875706
97278

−0.572

17:35161825
cg11331837
213402

−0.563
ACOT11
1:55014160
cg01802772
36934

−0.552
GNAS
20:57463991
cg09885502
188727

−0.527

11:28642652
cg26387458
460494

−0.511
HDAC11
3:13555664
cg26845082
468403

−0.506

3:22422855
cg20979384
374956

−0.484

1:204556835
cg13232075
244024

−0.478
AP2A2
11:1001560
cg16999994
311801

−0.463
ALS2CR12
2:202163482
cg07227024
141394

−0.463

4:82273176
cg07454933
145378

−0.456
CPO
2:207803547
cg17600943
321671

−0.455
FAM19A5
22:48896579
cg11019791
208228

−0.452
FHIT
3:60420416
cg16140565
297019

−0.443

6:75775380
cg15706692
289960

−0.439
ATP11A
13:113539522
cg21463262
382273

−0.435
PDHA2
4:96760945
cg10590622
201120

−0.433
CNTNAP5
2:124971544
cg01013522
21327

−0.432
COLEC11
2:3675155
cg10724632
203346

−0.432
RD3
1:211667751
cg22481673
397284

−0.424
RBM28
7:127950724
cg03119308
63402

−0.423

13:21896301
cg13730219
253914

−0.423

8:142283564
cg04123498
82844

−0.421
MYOCD
17:12562530
cg14192979
263428

−0.421
SLFN12
17:33734664
cg20086657
361521

−0.417

2:150845309
cg15958422
293993

−0.409
IFT43; TGFB3
14:76443578
cg21193926
378403

−0.405
FAM101A; NCOR2;
12:124810173
cg13127920
242348

ZNF664-

FAM101A

−0.403
SLC2A9
4:10009916
cg21795255
387383

−0.403
ATXN7L1
7:105306555
cg11957130
223895

−0.403
TRIM64C
11:49073835
cg06445586
125882

−0.400
HLA-A
6:29906977
cg26739327
466540

−0.394
SCN4B
11:118022607
cg22251955
394153

−0.392
LINC00254
16:1939295
cg10051493
191486

−0.391
MIR4457; TERT
5:1300309
cg14597862
271789

−0.390

14:22279816
cg16423096
302000

−0.384
RPL27A; SNORA3;
11:8714324
cg15828613
291887

SNORA45;

ST5

−0.382
MXRA7
17:74679597
cg03810198
76895

−0.378
CD82
11:44649802
cg21974656
390131

−0.377
BPIFA2
20:31755943
cg05840533
115130

−0.377
CCDC109B
4:110524473
cg17082366
313142

−0.375
TRIM24
7:138229989
cg12743416
236587

−0.374
RPTOR
17:78935070
cg17906851
326284

−0.371
KDM2B
12:121893769
cg07741840
150784

−0.370
HCG4B
6:29895204
cg26121931
455779

−0.369
NSMCE4A
10:123731471
cg19360212
349382

−0.369
NMNAT3
3:139397901
cg15295200
283344

−0.366

12:25454990
cg25134647
440489

−0.365

6:55778951
cg11290949
212735

−0.361
MRPL23
11:1985287
cg06258939
122771

−0.351

4:8569129
cg06991380
136538

−0.350
CDH4; MIR1257
20:60520624
cg16423285
302003

−0.349
MAST2
1:46420220
cg22337626
395319

−0.346
KIAA1908; PSMG3
7:1616229
cg23403836
412403

−0.346
SUMO3; UBE2G2
21:46220161
cg00272795
5810

−0.337
OR10K1
1:158435277
cg01463139
30452

−0.337
SLCO2B1
11:74861433
cg20704148
370892

−0.329
SPATS2L
2:201289756
cg17174466
314712

−0.327
SFT2D3; WDR33
2:128453335
cg03738707
75556

−0.325
HLA-DRB1
6:32555411
cg00598125
12786

−0.323
CCHCR1; PSORS1C2
6:31107186
cg07414487
144678

−0.322
HLA-A
6:29913343
cg19585676
353041

−0.320
LOC100628307
14:80858152
cg07572984
147668

−0.318
PSORS1C3
6:31148606
cg01982166
40677

−0.313
PTGER3; ZRANB2-
1:71511514
cg11418303
214891

AS1

−0.313

10:131209556
cg02372404
48486

−0.310

7:158750985
cg00413089
8734

−0.307
HCG4B
6:29894152
cg25644740
448500

−0.305

2:5605864
cg23233416
409551

−0.305
SLC47A2
17:19620263
cg08102564
157230

−0.302
SYS1; SYS1-
20:44007674
cg17811452
324650

DBNDD2; TP53TG5

−0.301
COL4A2
13:111115558
cg07618759
148582

−0.300
CDCA8; EPHA10
1:38180356
cg06437931
125736

−0.300
RPTOR
17:78809403
cg20502501
367732

−0.299
NDRG4
16:58534681
cg00758881
16033

−0.296
ITIH1; ITIH3
3:52828628
cg05393861
107345

−0.296
DPM2; FAM102A
9:130705120
cg01681863
34567

−0.295
TTC34
1:2710376
cg21783012
387180

−0.292
HCG4B
6:29895175
cg23681866
416899

−0.290
HCG4B
6:29895187
cg15411272
285048

−0.288
PSMD9; WDR66
12:122356390
cg21171335
377993

−0.286
BOC
3:112927486
cg27187580
474373

−0.286
MCF2L
13:113688132
cg15388766
284663

−0.285
B4GALNT4
11:364752
cg25497175
446150

−0.283

8:92570895
cg11420142
214927

−0.281

7:158751184
cg12744031
236605

−0.279

13:27077539
cg03531388
71371

−0.278
CASP7
10:115465924
cg01128042
23762

−0.278
HCG4B
6:29895260
cg24838316
435648

−0.278

2:69440951
cg02444957
49778

−0.277
OR51A2; OR51A4
11:4976263
cg25641451
448448

−0.274
FRMD4A
10:13972210
cg07629776
148782

−0.274

22:25571929
cg19707653
355076

−0.272
ATHL1; NLRP6
11:285037
cg22280068
394534

−0.269
SORBS2
4:186549051
cg09120722
175360

−0.267

11:5384517
cg26567385
463630

−0.265
MRPL44; WDFY1
2:224813276
cg15176306
281664

−0.265

19:29218101
cg04546413
91043

−0.264

10:47964834
cg16435686
302231

−0.264

7:158750244
cg12954512
239779

−0.263

16:14380714
cg03940883
79274

−0.262
B4GALT6
18:29205358
cg11986743
224388

−0.261
FBRSL1
12:133078117
cg23836570
419138

−0.259
LOC440905
2:130795582
cg18480627
335932

−0.257
SLC27A1
19:17600122
cg02707854
55128

−0.257

5:54117761
cg25997988
453719

−0.257
ATOH1
4:94759825
cg05893845
116159

−0.256
LOC100289473
20:1757570
cg03299990
66803

−0.252
COL18A1
21:46921982
cg05638648
111601

−0.251

7:1923695
cg12169700
227539

−0.250
C1orf86; PRKCZ
1:2121039
cg26227225
457598

−0.248

5:31106255
cg12908908
239081

−0.247
FAM157B
9:141105974
cg04824555
96218

−0.247

7:1976457
cg03075889
62651

−0.246
SLC6A3
5:1420305
cg07664579
149363

−0.245
ADAMTS2
5:178565001
cg01387905
28837

−0.243

7:136832262
cg05364766
106693

−0.241

19:13276344
cg19225953
347327

−0.241
PSMD9; WDR66
12:122356400
cg22618164
399325

−0.239

4:9479622
cg01394167
28957

−0.239

12:125411922
cg07877257
153188

−0.238

7:158750607
cg00815399
17228

−0.238
RNF213
17:78264297
cg11606607
217718

−0.237
TMEM39B
1:32535981
cg10312513
196231

−0.234
LPIN1
2:11888753
cg00523161
11124

−0.234
SGK110
19:56061334
cg18795732
340965

−0.232
LOC154822; VIPR2
7:158821175
cg25909532
452273

−0.231

7:158750384
cg11945929
223689

−0.229

1:161410551
cg22730047
401169

−0.228
PLEC
8:145003776
cg18000391
327713

−0.227

17:80849463
cg14195178
263473

−0.226
HOXA3; HOXA4;
7:27170394
cg19142026
346203

LOC100133311

−0.225

6:16962712
cg19300401
348504

−0.225
FAM66A
8:12237626
cg10206627
194443

−0.223
HTATIP2
11:20384377
cg26155681
456393

−0.221
AP2A2
11:970389
cg12893697
238836

−0.220
COL4A2
13:111111172
cg19218082
347212

−0.218
PAPLN
14:73712902
cg14834903
275901

−0.218
OSBPL5
11:3174092
cg06120313
120406

−0.217
C1orf86; PRKCZ
1:2120985
cg20300514
364680

−0.217

7:1367727
cg23896876
420086

−0.216
EGLN2; MIA-
19:41307778
cg21653913
385460

RAB4B; RAB4B;

RAB4B-

EGLN2

−0.216

13:80755568
cg00750481
15862

−0.216

5:176099987
cg11583351
217324

−0.215

5:125171542
cg12599971
234303

−0.215
MYO1D
17:31149877
cg01050010
22131

−0.213
DPYSL4; JAKMIP3
10:134001728
cg10144198
193247

−0.213

19:21863715
cg26562263
463546

−0.213
NDRG4
16:58533979
cg27113419
473118

−0.212
BMP4
14:54410717
cg16720578
307533

−0.210

5:134388224
cg03827835
77177

−0.209
C1orf86; PRKCZ
1:2121349
cg05337761
106096

−0.209
SFT2D3; WDR33
2:128453445
cg11059159
208817

−0.208
APOA1; APOC3;
11:116708413
cg09558982
183152

SIK3

−0.207
SFT2D3; WDR33
2:128453484
cg25277809
442618

−0.206

7:158750417
cg10079374
191993

−0.205

10:43522343
cg08461752
163848

−0.205
LASP1
17:37024042
cg20826740
372827

−0.204
NSUN4
1:46807113
cg17806798
324558

−0.204

1:149145082
cg16661522
306375

−0.204
PTP4A3
8:142427117
cg04687040
93680

−0.204

5:92414398
cg18783429
340738

−0.203
FLJ37453
1:16154831
cg21385522
381217

−0.203

12:132869069
cg05948955
117271

−0.202
RADIL
7:4854126
cg08799816
169789

−0.202

1:34615965
cg21440084
381930

−0.201
ARHGEF40; C14orf176;
14:21567333
cg00968545
20358

ZNF219

−0.200

7:1948755
cg16178271
297641

−0.199
TNS1
2:218707806
cg17588704
321484

−0.198
HLA-C
6:31241294
cg05338672
106118

−0.197
SLC27A1
19:17599784
cg17132030
313955

−0.196

11:19699299
cg18593660
337773

−0.196

16:1797050
cg07869343
153029

−0.195
GAS2L2; RASL10B
17:34067305
cg23633026
415965

−0.195

7:158790006
cg09640425
184513

−0.195
LRRC27
10:134150581
cg25076597
439582

−0.194
LOC440905
2:130795350
cg25180228
441163

−0.194
ZC3H12D
6:149785754
cg24131442
424218

−0.193
CES1
16:55867072
cg03744383
75666

−0.193
ACSF3
16:89152443
cg00324979
6844

−0.192

16:56000067
cg00991179
20841

−0.192
AP2A2
11:970664
cg06064525
119407

−0.192
CHTOP; S100A1;
1:153599704
cg11343894
213623

S100A13

−0.190
DBNL; PGAM2;
7:44104860
cg07075347
138233

POLM

−0.189
MYO10
5:16895511
cg02288345
46701

−0.189

19:29218262
cg14983838
278359

−0.189
EIF2D
1:206786180
cg21936179
389599

−0.189
FN3K; TBCD
17:80708632
cg02398342
49038

−0.188
TM7SF4
8:105342491
cg04554929
91221

−0.187
NXN
17:707141
cg20403644
366219

−0.187
NFATC1
18:77292443
cg06675417
130167

−0.186
KIAA1751
1:1886501
cg06090818
119880

−0.185
LOC100507055
12:133180238
cg26621607
464484

−0.185
SLC9A3
5:502291
cg14137381
262235

−0.184
CLDN22; CLDN24;
4:184250312
cg14241748
264522

WWC2

−0.184
MMD2
7:5000111
cg02276823
46453

−0.184
COL5A1
9:137691430
cg13889467
257004

−0.184

6:30000187
cg01915885
39235

−0.184
SLC47A2
17:19627822
cg12434897
231546

−0.183
KRTAP4-7
17:39240789
cg23827950
418999

−0.182

19:29218302
cg12756686
236783

−0.182
GAB2
11:78052863
cg24769381
434565

−0.182

13:33854227
cg15405588
284964

−0.182

13:112978703
cg19891452
358388

−0.180
C11orf53
11:111148753
cg27649396
482130

−0.179

19:29218774
cg03161606
64225

−0.178
ADAP1; COX19
7:1003645
cg08735705
168762

−0.178
MTG1; PAOX
10:135202877
cg06080948
119697

−0.177
NEUROG3
10:71339632
cg02330874
47587

−0.177
C10orf96
10:118084587
cg02721176
55417

−0.177
BAI1
8:143546858
cg02048922
41986

−0.176

8:119750651
cg26711508
466113

−0.176
GPR50
X:150351493
cg20071203
361302

−0.175
LARS2
3:45429626
cg13510812
249280

−0.175
TUBG2
17:40808068
cg24417155
428624

−0.175
OR12D2
6:29364799
cg25786333
450628

−0.174
RASA3
13:114872606
cg27086157
472626

−0.174
C21orf128; UMODL1
21:43529162
cg02489157
50718

−0.174
MYT1L
2:2119533
cg26383138
460416

−0.174

10:125751386
cg00502035
10662

−0.174

7:102134668
cg17207545
315260

−0.173
NRG1
8:32579253
cg20127899
362151

−0.173
CHTOP; S100A1;
1:153599671
cg13946767
258256

S100A13

−0.173
APOA1BP; IQGAP3;
1:156551787
cg09319828
178942

TTC24

−0.172
ATP11A
13:113413587
cg08484560
164316

−0.171
NKX2-3
10:101287609
cg10947831
206964

−0.171

5:171057282
cg10881242
205925

−0.171
ADAP1; COX19
7:1003710
cg12575883
233841

−0.171
CRAMP1L; HN1L
16:1722957
cg04245870
85306

−0.170
ADAMTS7
15:79107452
cg23450377
413109

−0.170
PCSK6
15:101932559
cg27370471
477437

−0.170

19:1737123
cg08692111
167944

−0.170
C5orf38; IRX2
5:2743124
cg18803147
341088

−0.169
BAI1
8:143581481
cg26953288
470357

−0.169
STK32B
4:5374425
cg14422932
268145

−0.168

X:152584950
cg03201165
64963

−0.168
POU5F1; PSORS1C3
6:31146845
cg20073472
361344

−0.168
NDRG4
16:58534708
cg04484415
89876

−0.168
FAM20C
7:194798
cg12042135
225245

−0.167
EDN1
6:12292676
cg27565517
480713

−0.167
C1QTNF8
16:1152511
cg06394109
125022

−0.167
KLK5; KLK6
19:51456308
cg00768359
16234

−0.166
ADAP1
7:961457
cg06589239
128495

−0.166

11:134892703
cg21757617
386803

−0.166
HOXA3; HOXA4;
7:27170892
cg14359292
266882

HOXA5; LOC100133311

−0.165
LCP1
13:46757415
cg06477663
126420

−0.165
SPAG11A
8:7720259
cg23703303
417310

−0.165

19:21767566
cg19051117
344954

−0.165
OR10R2
1:158450237
cg04132017
83014

−0.165
LOC284661
1:4481995
cg20252997
363933

−0.164
FHOD3
18:34327498
cg21367586
380971

−0.164
PCDHB4
5:140501812
cg06048354
119137

−0.164
HLA-DQB2
6:32729174
cg04418355
88678

−0.164

6:28447087
cg26968378
470632

−0.163
BAI1
8:143580965
cg09544050
182856

−0.163
LOC440905
2:130794753
cg25239986
442097

−0.163
SPINK5
5:147473666
cg04829448
96297

−0.163
ZNF718
4:124342
cg12717203
236185

−0.163
TIAM2
6:155464712
cg24207161
425489

−0.162
PACS2
14:105830721
cg19499452
351610

−0.162
MCTS1
X:119738550
cg00357087
7563

−0.162
RASA3
13:114900021
cg06611532
128857

−0.161

4:187984958
cg19632603
353880

−0.160
ITGA11
15:68713677
cg02454536
49961

−0.160
ACAP1; KCTD11;
17:7253720
cg02676175
54546

TMEM95

−0.160
HAAO
2:43023945
cg14631114
272427

−0.160
WWP2
16:69830414
cg03424554
69244

−0.160
PGRMC2
4:129212177
cg02096220
43042

−0.159
SHISA6
17:11142733
cg23474049
413465

−0.159

6:28447107
cg12584458
233995

−0.159
ZP2
16:21222939
cg18249108
332126

−0.159
CLCNKA; HSPB7
1:16349079
cg08231696
159747

−0.158
SPINK7
5:147699718
cg08859406
170938

−0.158
GNAS
20:57463503
cg11480267
215775

−0.158
STX2
12:131303247
cg11011512
208090

−0.158
ADCK4
19:41208803
cg07615236
148518

−0.158

6:148540308
cg21796170
387391

−0.158
NDRG4
16:58534157
cg05725404
113149

−0.157
ANXA9; CERS2
1:150954826
cg13320146
245435

−0.157
SAMD3
6:130504413
cg24048806
422810

−0.157
TCL6
14:96129574
cg05093429
101497

−0.157

6:55761410
cg17273096
316241

−0.156
B3GNTL1
17:81008971
cg17652174
322327

−0.156
RNF219
13:79234251
cg01819759
37343

−0.156
GGNBP2; MYO19;
17:34891843
cg02097479
43078

PIGW

−0.156

7:79964738
cg22110839
392010

−0.156
HOXA3; HOXA4;
7:27170412
cg11410718
214730

LOC100133311

−0.155

6:58777827
cg26951520
470325

−0.155
KIRREL3-
11:126872863
cg17273911
316252

AS3

−0.155
NRXN1
2:51260399
cg00345522
7288

−0.155

14:106025958
cg27055313
472099

−0.155

4:60001000
cg11281224
212579

−0.154

4:9479947
cg12006118
224679

−0.154
IL12RB1
19:18170383
cg26642774
464790

−0.154

1:22599443
cg07371337
143948

−0.154
ZNF845
19:53828996
cg22256944
394221

−0.154

13:112705636
cg01896130
38843

−0.154
HOTAIR; HOXC12
12:54354590
cg05573844
110417

−0.154

13:61758710
cg15508935
286618

−0.154
MICA
6:31382027
cg20144487
362399

−0.153

6:156983263
cg05282260
105071

−0.153
MIR1283-
19:54199538
cg26325497
459342

1; MIR518B; MIR518F;

MIR519B;

MIR519C;

MIR520A; MIR520B;

MIR523;

MIR525; MIR526A1;

MIR526B

−0.153
MKX
10:28030033
cg13806489
255420

−0.153

10:53639124
cg06976598
136324

−0.153
CHTOP; S100A1;
1:153600156
cg07898899
153567

S100A13

−0.152

11:24346161
cg05202300
103488

−0.152
LOC728613
5:1641766
cg08769156
169313

−0.152
LOC100506388;
17:184106
cg15996459
294655

RPH3AL

−0.151
PALMD
1:100111849
cg24603803
431699

−0.151
HCG4B
6:29895116
cg15671450
289296

−0.151

8:88760082
cg05893029
116145

−0.150
GPR158
10:25620462
cg01006048
21182

−0.150

14:95155784
cg16462006
302671

−0.150
PALM2; PALM2-
9:112562314
cg13690280
253070

AKAP2

−0.150
LOC100507055;
12:133185615
cg18833933
341613

P2RX2

−0.150
IGF2; IGF2-
11:2154132
cg11717189
219595

AS; INS-

IGF2; MIR483

−0.149
MYO16
13:109833854
cg10697882
202881

−0.149
SUMO3
21:46239952
cg22595657
398990

−0.149
EME2; MRPS34;
16:1822124
cg09540102
182804

NME3; SPSB3

−0.149
TTLL10
1:1118157
cg16366262
300931

−0.149

7:158269409
cg17429772
318912

−0.149

12:133003907
cg04741728
94673

−0.148
SHANK2
11:70493931
cg05794931
114366

−0.148
CRTAC1
10:99734513
cg19421526
350393

−0.148
PXDN
2:1734344
cg12760299
236833

−0.148

6:28447115
cg21903646
389050

−0.148
GGNBP1; LINC00336
6:33561099
cg04329454
86936

−0.148
CLGN
4:141317067
cg22901919
403995

−0.147
COL11A2; RXRB
6:33158020
cg16507569
303394

−0.147

7:93960063
cg01827933
37531

−0.147
LHX6
9:124983482
cg13832372
255929

−0.147
ISL1
5:50688913
cg26293019
458765

−0.147
DBNL; PGAM2;
7:44105050
cg16627090
305718

POLM

−0.147

3:193587490
cg21197336
378486

−0.147

14:107095056
cg07958169
154668

−0.147
SNED1
2:241975140
cg09991306
190473

−0.147
HOXA3; HOXA4;
7:27170755
cg03724423
75252

HOXA5; LOC100133311

−0.147
SEPT3; WBP2NL
22:42395067
cg22189786
393238

−0.147

2:208541770
cg03716125
75048

−0.146

5:66541588
cg11553311
216848

−0.146
KTN1; KTN1-
14:56046098
cg16907514
310470

AS1

−0.146
FAM116B; PLXNB2
22:50753068
cg20435485
366698

−0.146
HOXA3; HOXA4;
7:27170388
cg07317062
142981

LOC100133311

−0.145
HLA-A
6:29911295
cg09535358
182715

−0.145
ARNTL
11:13302098
cg13286116
244869

−0.145
MSH5; MSH5-
6:31731881
cg03392100
68641

SAPCD1; SAPCD1;

VWA7

−0.145
IL31; LRRC43
12:122651623
cg14874216
276626

−0.145
MSH5; MSH5-
6:31734192
cg13187827
243288

SAPCD1; SAPCD1;

VWA7

−0.144
SERPINB6
6:2972435
cg08155050
158293

−0.144
DLGAP2
8:1455764
cg10636144
201951

−0.144
SAMD11
1:869368
cg13692836
253138

−0.144
RPH3AL
17:146926
cg04172345
83843

−0.144

1:228743235
cg12437277
231594

−0.143

17:79455736
cg09841001
187897

−0.143
C11orf53; C11orf92
11:111155021
cg03554573
71909

−0.143
ATXN1
6:16413624
cg11291305
212741

−0.143
FEM1A
19:4785374
cg14818248
275598

−0.143
HLA-A
6:29912713
cg18349863
333730

−0.143
TP73
1:3600879
cg17471939
319626

−0.143

1:2863815
cg25137787
440554

−0.143
ARNT2
15:80824318
cg19708986
355104

−0.143

13:99084682
cg03040740
61905

−0.143

6:28446840
cg01792601
36700

−0.142
LRRC15
3:194091167
cg07048348
137676

−0.142

1:37231474
cg21952052
389839

−0.142
DFNA5
7:24742552
cg25709790
449401

−0.142
PACS2
14:105830606
cg12425861
231390

−0.142
INPP5K; LOC100306951;
17:1412950
cg07185664
140562

PITPNA

−0.141
LOC100506388;
17:184131
cg24871089
436253

RPH3AL

−0.141
DDX58
9:32525315
cg14286514
265460

−0.141

7:158789849
cg19418458
350346

−0.141
ARHGAP30; PVRL4
1:161042063
cg00862398
18157

−0.141
IKZF3; ZPBP2
17:38024146
cg16810031
309049

−0.141

17:21416281
cg00007215
167

−0.141

8:23605601
cg03324961
67319

−0.141
PDE6B
4:645781
cg01132407
23844

−0.140
HHIPL1
14:100130465
cg18678107
339014

−0.140
MTG1; PAOX
10:135202906
cg24644436
432348

−0.140
CES1
16:55866757
cg03880033
78129

−0.139
TLX1NB
10:102872719
cg17034508
312397

−0.139
PCDHB17; PCDHB6
5:140530410
cg23247945
409860

−0.139
TMEM100
17:53800484
cg18040354
328429

−0.139
PRKG2
4:82075193
cg22772235
401742

−0.139
SEL1L2
20:13830102
cg17971895
327285

−0.139

5:74908142
cg19683494
354666

−0.139

2:131010647
cg27624826
481683

−0.139
HIPK4; PRX
19:40904691
cg24923931
437130

−0.138
SCN7A
2:167350883
cg14771658
274784

−0.138

15:98196247
cg19459332
350984

−0.137
PMPCA; SDCCAG3;
9:139299357
cg14108380
261681

SNAPC4

−0.137

16:62984521
cg02248103
45873

−0.137
CYB5D2; ZZEF1
17:4043867
cg04417708
88669

−0.137
CST11; CSTL1
20:23433608
cg11657817
218579

−0.137
CTC1; LINC00324
17:8124867
cg20250341
363887

−0.137
CNR2; FUCA1
1:24195143
cg24792360
434918

−0.137
PKNOX2
11:125170859
cg23418965
412666

−0.137
PAX2
10:102592366
cg03286031
66537

−0.137
TEX2
17:62341028
cg18312782
333101

−0.137

2:226913713
cg05293897
105270

−0.136
TMEM72-AS1
10:45374906
cg20638675
369712

−0.136
HLA-DQB2
6:32729130
cg07180897
140474

−0.136
ALK
2:29751968
cg01412762
29371

−0.136

19:29218732
cg12667521
235503

−0.136
TOX2
20:42548586
cg20889774
373555

−0.136
RECK
9:36036514
cg13392078
246714

−0.136
MIR593
7:127720749
cg20426275
366531

−0.136
ODZ4
11:78948859
cg12642289
235052

−0.136
MTERF
7:91510405
cg16284459
299467

−0.136
RBFOX3
17:77302162
cg08223357
159591

−0.136

18:44770781
cg24371990
427906

−0.136
CACNA1C
12:2696048
cg08166587
158536

−0.136
DAB1
1:58089001
cg00026909
659

−0.135

6:156983304
cg08839808
170533

−0.135
MTG1; PAOX
10:135202839
cg17143376
314138

−0.135
PIP5K1A; VPS72
1:151170427
cg24720336
433732

−0.135
ANKS3; C16orf71;
16:4793770
cg00605362
12928

ZNF500

−0.135

11:91950460
cg20506843
367791

−0.135
RTN4RL1
17:1835482
cg23676314
416771

−0.135

2:10984512
cg00442205
9317

−0.134
ZDHHC13
11:19138045
cg00161556
3630

−0.134
PAPLN
14:73712491
cg09636214
184437

−0.134
CTRB2
16:75242114
cg08467866
163985

−0.133
ZNF718
4:125112
cg10197305
194260

−0.133
IGF2; IGF2-
11:2154113
cg13165070
242895

AS; INS-

IGF2; MIR483

−0.133

2:38099030
cg02752932
56067

−0.133
TACC2
10:123873748
cg23828763
419014

−0.133

7:115116310
cg04544267
91006

−0.133
CES1
16:55866997
cg23196985
408839

−0.133
CCDC105
19:15121385
cg18739061
339959

−0.133

19:43203368
cg24333150
427217

−0.132
FXYD2; FXYD6-
11:117696743
cg11820026
221463

FXYD2

−0.132
DAB2IP
9:124363848
cg21234082
379229

−0.132
LOC100289187
7:99195819
cg12290671
229416

−0.132
OCA2
15:28014040
cg15194100
281887

−0.132
NAV1
1:201644923
cg24253904
426103

−0.132
SLC24A6
12:113773298
cg12583184
233973

−0.131

3:42265641
cg18812386
341259

−0.131
GREB1; MIR4429
2:11680020
cg11534680
216555

−0.131
TXNRD1
12:104676774
cg15775217
291055

−0.131
CCBL2; RBMXL1
1:89459529
cg11309454
213030

−0.131
GPR12
13:27338713
cg14339397
266524

−0.131

9:34810228
cg13923371
257761

−0.131
IFI44; IFI44L
1:79114976
cg07107453
138862

−0.130

5:171057196
cg07871442
153079

−0.130
OVCH2
11:7709186
cg25833922
451333

−0.130
PSMD11
17:30770961
cg09309269
178739

−0.130
DEFA4; DEFA6
8:6783521
cg02932321
59694

−0.130
TEPP
16:58016655
cg01479664
30752

−0.130
IL28B
19:39737768
cg04722177
94275

−0.130
IL20RA
6:137366545
cg08823985
170226

−0.130
PA2G4; RPL41;
12:56509603
cg18500368
336269

ZC3H10

−0.129

14:26338282
cg16725552
307629

−0.129
ATHL1; NLRP6
11:281516
cg06432119
125636

−0.129
GIMAP4
7:150264767
cg08960815
172781

−0.129
KLHL29
2:23839710
cg01387450
28832

−0.129

12:114701413
cg10233830
194930

−0.129

2:62521325
cg22770637
401725

−0.129
ALK
2:30142677
cg00643897
13652

−0.129
SEMA5B
3:122712271
cg11160908
210504

−0.129
TTF2
1:117604726
cg19319037
348805

−0.129
C20orf54
20:741798
cg19037007
344707

−0.129

12:69725435
cg22375663
395880

−0.129

8:41585554
cg17182837
314877

−0.128

3:118144311
cg20207443
363278

−0.128
LINC00299
2:8444004
cg18854004
341911

−0.128

11:106239635
cg01152624
24270

−0.128
GNAS; GNAS-
20:57431202
cg09437522
181002

AS1

−0.128

13:112978683
cg20923605
374019

−0.128
MITF
3:69915302
cg03831180
77231

−0.128
PTN
7:137029097
cg15284177
283213

−0.128

1:149155792
cg27554973
480528

−0.127
ENTPD1; LOC728558
10:97624891
cg09217157
177016

−0.127
ZFPM1
16:88536950
cg05183538
103174

−0.127
CCDC64B; HCFC1R1;
16:3079953
cg07063883
137997

THOC6;

TNFRSF12A

−0.127
APOA1BP; IQGAP3;
1:156551873
cg01010328
21258

TTC24

−0.127
NRG1
8:32076032
cg23964820
421269

−0.127
MTG1; PAOX
10:135203102
cg18563886
337268

−0.127

13:112984840
cg27260867
475484

−0.127
AKAP8; AKAP8L
19:15488902
cg22765626
401667

−0.127

18:37379468
cg15612221
288285

−0.127

17:21416258
cg10674575
202559

−0.127

13:100583872
cg07223206
141319

−0.126
KLK1; KLK15
19:51334890
cg26325285
459337

−0.126
GALNT9; LOC100130238
12:132859608
cg10173694
193804

−0.126
ATG4C
1:63249199
cg24082680
423369

−0.126

7:102330635
cg06322601
123757

−0.126

3:73723546
cg02131018
43720

−0.126
HIPK4; PRX
19:40904851
cg00478479
10159

−0.126
GNAT1; SLC38A3
3:50242325
cg15335139
283889

−0.126
CYP4F30P
2:131451149
cg14204395
263669

−0.126

16:88804051
cg26748794
466680

−0.126
HUNK
21:33242495
cg15636421
288718

−0.125
KLHL29
2:23840282
cg17129809
313908

−0.125
MEIS1
2:66657913
cg10835286
205203

−0.125
NUP98; PGAP2
11:3817849
cg19247588
347686

−0.125
MIR4287; SCARA5
8:27735178
cg04214878
84655

−0.125
SPINK7
5:147699892
cg13022905
240779

−0.125
PTH1R
3:46936655
cg02527881
51488

−0.125
GIMAP4
7:150264987
cg00323915
6821

−0.125
PTHLH
12:28120054
cg20389635
366021

−0.125
EIF2D
1:206786174
cg16966520
311311

−0.124

7:27475596
cg10070328
191836

−0.124

1:161409970
cg00975746
20506

−0.124
KCNK10
14:88791298
cg02883668
58609

−0.124

15:34788847
cg10767425
203961

−0.124

8:49044542
cg11491002
215895

−0.124
DLGAP4
20:35064637
cg01463540
30456

−0.124
HSP90B3P
1:92099858
cg04090794
82132

−0.124
NOSIP; PRRG2
19:50084626
cg21913888
389236

−0.124
ISL1
5:50692281
cg24549912
430883

−0.124
STC2
5:172751331
cg01984743
40717

−0.124

2:72079276
cg07258910
141932

−0.123
PKD1L2
16:81254169
cg03406106
68931

−0.123
ANO4
12:101187093
cg25027699
438862

−0.123
TRIM21
11:4415203
cg07244098
141703

−0.123
MRPL38; TRIM65
17:73892097
cg01453052
30258

−0.123
BTN3A3
6:26442290
cg12537337
233273

−0.123
LOC100129620;
1:99469634
cg24373253
427922

LPPR5

−0.123
FYN
6:112165062
cg26846943
468428

−0.123
ASB1
2:239334832
cg08773314
169376

−0.123
FAM163A
1:179713788
cg14748380
274436

−0.122
KIAA1143; KIF15
3:44802604
cg09333631
179217

−0.122
MAP3K7
6:91297516
cg18683523
339091

−0.122

4:9382953
cg02136252
43830

−0.122

5:141616065
cg24749559
434242

−0.122

15:101389733
cg07035436
137452

−0.122

5:72510846
cg26653990
465004

−0.122

17:78955599
cg11521079
216324

−0.122

2:227476235
cg08982961
173162

−0.122
LRRC27
10:134150542
cg22586726
398883

−0.122
EXOC7; GALR2;
17:74073876
cg07909178
153763

SRP68; ZACN

−0.121
TAF3
10:7859768
cg09994553
190530

−0.121
CDK12; MED1
17:37608096
cg15445000
285571

−0.121
HLA-
6:33043849
cg22483030
397307

DPA1; HLA-

DPB1

−0.121
NUBP1
16:10837135
cg09079882
174735

−0.121
TSLP
5:110407538
cg15739437
290539

−0.121
PSMD9; WDR66
12:122356598
cg21016266
375557

−0.121
DOK7
4:3487436
cg15652666
289019

−0.121
OR6B3; PRR21
2:240985618
cg10906826
206344

−0.121
FBLN7
2:112898400
cg09982942
190323

−0.120
CXCR7
2:237478664
cg03626672
73351

−0.120
MBTPS2
X:21858304
cg21195120
378430

−0.120
NLRP3; OR2B11
1:247616686
cg14830002
275801

−0.120
CTAGE11P
13:75814496
cg17109374
313605

−0.120

5:177395755
cg11264997
212321

−0.120
GAS7; RCVRN
17:9805074
cg26853458
468546

−0.120
GAD2
10:26531942
cg23052437
406538

−0.120
LCE2A
1:152670843
cg13697387
253231

−0.120
SPDYC
11:64936920
cg23079866
407032

−0.119
SPTBN2
11:66487938
cg04883026
97440

−0.119
HOTTIP; HOXA11-
7:27236674
cg01363170
28338

AS1; HOXA13

−0.119
SYS1; SYS1-
20:43991402
cg00385441
8134

DBNDD2

−0.119
ZNF876P
4:204382
cg00569896
12104

−0.119
CCDC71; KLHDC8B
3:49203081
cg18590502
337716

−0.119
GRAMD2
15:72448319
cg12252008
228855

−0.119

16:76228294
cg06827491
133242

−0.119
LOC116437
12:131645153
cg07374109
143989

−0.119
CACNG4
17:64973939
cg23968154
421320

−0.119
NAV1
1:201619295
cg04179952
83989

−0.119

12:58934471
cg01919941
39316

−0.119

13:21893289
cg21970626
390084

−0.119
ANXA9; FAM63A
1:150969592
cg21859421
388363

−0.119

1:10895517
cg17480077
319783

−0.118
LRRC27
10:134150489
cg21370255
381012

−0.118
POTEA
8:43147397
cg26969150
470647

−0.118
HOXA3; HOXA4;
7:27170313
cg04317399
86720

LOC100133311

−0.118
C1orf86; PRKCZ
1:2121449
cg08200543
159156

−0.118

8:81143546
cg16745033
307963

−0.118

7:136362483
cg11678250
218935

−0.118
SPIN2B
X:57147918
cg12074688
225883

−0.118

8:144152376
cg17001448
311828

−0.118
ASPHD1; KCTD13;
16:29912700
cg10093648
192261

SEZ6L2

−0.118
EIF2D
1:206786178
cg16639185
305935

−0.118
PXN
12:120688744
cg22564731
398621

−0.118
MIR4757; OSR1
2:19553950
cg00954878
20061

−0.118
PROX1
1:214152805
cg26054764
454613

−0.117
CDH3
16:68691561
cg09821218
187538

−0.117
LPP
3:188115336
cg23651889
416316

−0.117

5:72666838
cg11316517
213156

−0.117
DSCR3
21:38630506
cg18380783
334168

−0.117

7:136190456
cg03439301
69540

−0.117
TMEM100
17:53800554
cg03233426
65601

−0.117
PSMD11
17:30770932
cg20190559
363067

−0.117

5:171057078
cg11620716
217943

−0.117
FN3K; TBCD
17:80708513
cg00809820
17098

−0.117
SECTM1
17:80285515
cg05744064
113450

−0.117
NCOA1
2:24806444
cg23648923
416268

−0.117
LOC100128398;
19:58515046
cg09577391
183474

ZNF606

−0.117
LOC100289187
7:99195788
cg24024660
422355

−0.117

16:77535527
cg06794141
132525

−0.117

2:192792315
cg01836906
37718

−0.117
LELP1
1:153175842
cg00298977
6302

−0.117
ODF1
8:103556749
cg27000960
471198

−0.117
GCK
7:44229319
cg16476432
302901

−0.117

11:2211939
cg19586845
353065

−0.117
HCG4; LOC554223
6:29761905
cg25193571
441364

−0.117
CTNND2
5:11588971
cg01937840
39702

−0.116
MYOM2
8:1994478
cg20219329
363455

−0.116

15:30337018
cg14398295
267622

−0.116
RASAL1
12:113574368
cg16890739
310176

−0.116

15:36699121
cg02763009
56272

−0.116
BIRC7; FLJ16779;
20:61878032
cg12649455
235197

MIR3196;

NKAIN4

−0.116

7:1250246
cg07034004
137422

−0.116

5:170763642
cg23036405
406232

−0.116
NCR1
19:55417647
cg12952132
239747

−0.116

1:22591361
cg13048466
241145

−0.115
GLP1R
6:39015339
cg19772011
356340

−0.115
RGMA
15:93615146
cg21079003
376460

−0.115
PGM5P2
9:69148624
cg18861917
342052

−0.115
ZBED4
22:50250283
cg20618087
369398

−0.115
LARS2
3:45429742
cg04459086
89409

−0.115
TACC2
10:123886914
cg26111575
455575

−0.115
ST8SIA2
15:92939006
cg08289525
160900

−0.115
ANO7
2:242147702
cg00255732
5474

−0.115
LRRC34; LRRIQ4
3:169531864
cg10994914
207829

−0.115

14:88097221
cg26252794
458035

−0.115
DGKB
7:14415317
cg03229767
65553

−0.114
LRRC27
10:134150690
cg02535060
51631

−0.114
LOC100131138
12:111374169
cg09792970
187023

−0.114
CNNM2
10:104676907
cg15439196
285445

−0.114
CCNYL1
2:208572165
cg18757817
340266

−0.114
PRRX1
1:170631847
cg22693806
400548

−0.114

11:44489577
cg03708694
74912

−0.114
DKFZp434L192
7:56563820
cg21216010
378877

−0.114
NRP1
10:33612892
cg17425818
318845

−0.114
TFCP2
12:51570174
cg21570277
384054

−0.114
LHX6
9:124982834
cg17930194
326612

−0.114
MMP17
12:132317128
cg01830463
37580

−0.114
LRRC27
10:134150567
cg07119315
139090

−0.114

8:67317506
cg02934300
59732

−0.114
DBNL; PGAM2;
7:44105721
cg21088488
376592

POLM

−0.114

1:113425263
cg10541466
200276

−0.114
AGAP1
2:236774164
cg03785646
76466

−0.114

7:73424891
cg09076650
174691

−0.114

6:1449399
cg18182981
331002

−0.114
NDUFA12
12:95397704
cg22141781
392510

−0.114
HOXA3; HOXA4;
7:27170880
cg04321618
86813

HOXA5; LOC100133311

−0.113
MIR4283-
7:63085215
cg10945855
206928

1; MIR4283-2

−0.113
PPIL2
22:22020076
cg04983276
99379

−0.113

2:72079413
cg24516106
430249

−0.113

10:125222790
cg11653519
218499

−0.113

7:21209781
cg08701183
168131

−0.113
MTG1; PAOX
10:135202522
cg10902549
206273

−0.113
NR2F1
5:92927796
cg26067259
454804

−0.113

2:218048915
cg00549040
11649

−0.113
GRK4
4:3043527
cg01807241
37046

−0.113
TNXB
6:32066446
cg14011987
259623

−0.113
SNED1
2:241975756
cg26707709
466046

−0.113

6:28446794
cg03350138
67869

−0.113
C6orf48; HSPA1B;
6:31806478
cg17794996
324365

SNORD48;

SNORD52

−0.113
CBX7
22:39545030
cg18708252
339475

−0.113
UPF2
10:12085641
cg00513208
339475

−0.113

17:80860250
cg04497611
90135

−0.112
DMD
X:31285129
cg06746884
131521

−0.112
FGF4
11:69587473
cg26765567
466900

−0.112

6:30419373
cg03507875
70857

−0.112

19:29217858
cg25267487
442467

−0.112

16:84953424
cg01765164
36115

−0.112
DGKG
3:185912486
cg18172135
330799

−0.112

13:111451972
cg22731513
401204

−0.112
FZD1
7:90895894
cg08714590
168374

−0.112
CLCN7
16:1524255
cg08008072
155549

−0.112
CRX
19:48324309
cg06945747
135695

−0.112

1:91227319
cg08895590
171690

−0.112
KALRN
3:124232190
cg06690085
130439

−0.112

9:128799328
cg13946341
258251

−0.112
IL34; MTSS1L
16:70688171
cg02602352
52989

−0.112
TMEM171
5:72431891
cg01170694
24642

−0.112

17:42706084
cg14836839
275934

−0.112
RASGEF1C
5:179634671
cg12408990
231108

−0.112
DOK7
4:3486116
cg00752263
15898

−0.112
ANAPC2; GRIN1;
9:140062197
cg03206445
65043

LRRC26;

MIR3621

−0.111
OR6Q1; OR9Q1
11:57792403
cg18886347
342489

−0.111
BAI1
8:143580823
cg05758861
113684

−0.111

2:121280002
cg00314115
6610

−0.111
MUC22
6:30980847
cg27292220
475981

−0.111
AGAP1
2:236773924
cg15981851
294380

−0.111

6:55774999
cg19318364
348791

−0.111
ITIH1; ITIH3
3:52824283
cg18404041
334584

−0.111
PDE6B
4:648752
cg17643796
322207

−0.111
TRIM7
5:180614858
cg25606201
447878

−0.111

8:141490124
cg15842218
292164

−0.111
IPMK
10:59949191
cg09039685
174085

−0.111
CCDC129
7:31685368
cg02943305
59917

−0.111

5:1645640
cg11628972
218045

−0.111
CDHR3
7:105596715
cg27099486
472857

−0.111
DCX
X:110654011
cg11031647
208426

−0.111
PLA2G4D
15:42371967
cg02760164
56222

−0.111
ANKRD34C
15:79576704
cg14577319
271361

−0.110

1:161391807
cg00056433
1344

−0.110
FHL3; SF3A3
1:38460950
cg05202204
103487

−0.110

5:72485634
cg14727987
274140

−0.110

11:41481578
cg24638253
432227

−0.110

6:27521330
cg26264769
458241

−0.110

5:177592761
cg25087499
439729

−0.110

14:103783717
cg10559742
200586

−0.110
ARL4C
2:235406291
cg05308656
105595

−0.110
HHIP; LOC646576
4:145566595
cg02524475
51415

−0.110
C11orf9
11:61545187
cg07136108
139453

−0.110
PCDHA1; PCDHA10;
5:140238079
cg18906028
342772

PCDHA11;

PCDHA2;

PCDHA3; PCDHA4;

PCDHA5;

PCDHA6;

PCDHA7; PCDHA8;

PCDHA9

−0.110
LOC151171
2:239463229
cg10182060
193967

−0.110

14:22385890
cg16138400
296975

−0.110
MAGIX; PLP2;
X:49027884
cg22366498
395712

PRICKLE3

−0.110
COL1A1
17:48288538
cg06769994
132032

−0.110
FAM70A
X:119443941
cg26583344
463923

−0.110
CXCR2
2:219001517
cg10819992
204935

−0.110

16:66162203
cg26798936
467489

−0.110
CCHCR1; PSORS1C2
6:31105872
cg03034365
61773

−0.110

3:36675685
cg12870891
238511

−0.110
DEFB135; DEFB136
8:11838843
cg12807628
237566

−0.110
MDC1; TUBB
6:30684572
cg10925640
206607

−0.110
CLDN4; WBSCR27
7:73256416
cg03781731
76399

−0.110
SNRPN
15:25123381
cg08560373
165668

−0.109
FBXL16; METRN
16:757149
cg07644125
149038

−0.109
EIF2D
1:206786170
cg21155316
377647

−0.109

8:135726252
cg00057272
1361

−0.109

13:112979998
cg20620751
369432

−0.109
DHRS7
14:60629192
cg06898279
134753

−0.109
EFS; IL25
14:23835595
cg17205324
315223

−0.109
PALMD
1:100111727
cg07960762
154721

−0.109

10:79470169
cg19094530
345528

−0.109
ARHGEF6
X:135863582
cg01134144
23879

−0.109
DUS3L
19:5799340
cg20467412
367204

−0.109
RGMA
15:93633408
cg04697454
93855

−0.109
VWA5B1
1:20608736
cg16713551
307396

−0.109

14:106791268
cg14042931
260352

−0.109

19:1673498
cg10697737
202878

−0.109
GPR4; OPA3
19:46097075
cg16620032
305585

−0.109
LOC388630
1:48452740
cg07202054
140866

−0.108
HK3; UNC5A
5:176314628
cg06783121
132285

−0.108

6:12342070
cg03519011
71096

−0.108
C12orf73; TDG
12:104350162
cg22927789
404375

−0.108
CDH22
20:44882514
cg25558663
447055

−0.108

6:18752614
cg00664117
14044

−0.108
ARHGEF25; B4GALNT1;
12:58011837
cg00700412
14808

DTX3;

SLC26A10

−0.108
SHANK2
11:70564414
cg13080721
241684

−0.108
LOC154449
6:170571686
cg18698681
339306

−0.108
KCNH2
7:150644459
cg01559770
32264

−0.108
TMEM132D
12:130384734
cg08261450
160299

−0.108
DUOX1; DUOXA1
15:45427034
cg14918338
277309

−0.108
DNAJB13
11:73661250
cg02070028
42486

−0.108
PSMD7
16:74331618
cg09313046
178793

−0.108
LGR6
1:202172778
cg04811114
95994

−0.108

13:69557960
cg18586262
337639

−0.108

1:201316444
cg26233753
457728

−0.108

1:37139265
cg20745381
371614

−0.108

10:121837310
cg10087780
192116

−0.108

15:98196234
cg08064292
156507

−0.107
GUCY2E; LRRC32
11:76381800
cg19752094
355941

−0.107
LOC440910
2:132057004
cg07051654
137739

−0.107
NAPSA
19:50861262
cg12273319
229159

−0.107
TRIM69
15:45028270
cg10439456
198368

−0.107
CHTOP; S100A1;
1:153599831
cg02331910
47613

S100A13

−0.107

5:132938694
cg19005955
344221

−0.107
ACOT11; FAM151A
1:55096622
cg22619910
399357

−0.107
CRYBA2; FEV;
2:219851181
cg18664514
338819

LOC151300

−0.107
C10orf96
10:118084504
cg13836550
255997

−0.107
SORCS3
10:106749483
cg26349484
459830

−0.107
ZEB2; ZEB2-
2:145273345
cg04640885
92836

AS1

−0.107
GALNT6
12:51786489
cg15127250
280846

−0.107

3:137187558
cg24821307
435362

−0.107
ADORA1
1:203086869
cg18811731
341246

−0.107
OR1J4; OR1N1
9:125289357
cg14598387
271804

−0.107
CARTPT
5:71012177
cg11927345
223348

−0.107
HCRT; KCNH4
17:40330907
cg06514003
127062

−0.107
SNRPN
15:25093366
cg02171545
44484

−0.107
C2orf28; CAD;
2:27434262
cg14242246
264531

SLC5A6

−0.107
HOXA3; HOXA4;
7:27170552
cg16651126
306141

LOC100133311

−0.107

15:20562413
cg03344283
67729

−0.106
PLA2G7
6:46703670
cg12854458
238255

−0.106
MAG
19:35790951
cg25443560
445295

−0.106
HLA-DRB1
6:32552022
cg10765922
203924

−0.106
FAM83H; MAPK15
8:144801088
cg05626536
111385

−0.106

3:193987757
cg16282892
299443

−0.106
POU4F2
4:147573410
cg05710982
112882

−0.106
DKFZp434J0226
19:46712075
cg00537984
11421

−0.106
GPR31
6:167571630
cg25285053
442729

−0.106
PCDHA1; PCDHA10;
5:140248610
cg25024993
438807

PCDHA11;

PCDHA12;

PCDHA2; PCDHA3;

PCDHA4;

PCDHA5;

PCDHA6; PCDHA7;

PCDHA8;

PCDHA9

−0.106
SGPP2
2:223288637
cg11300809
212887

−0.106
DLC1
8:13373090
cg00933411
19610

−0.106
PRSS55
8:10386222
cg10657228
202268

−0.106
ZIC1; ZIC4
3:147120248
cg13897134
257142

−0.106
DKFZp434L192
7:56563742
cg17876758
325825

−0.106
C11orf10; C11orf9
11:61548003
cg19617373
353600

−0.106

6:99075228
cg05593122
110762

−0.106

14:104787388
cg05210671
103662

−0.106
HHLA2
3:108041508
cg24769830
434575

−0.106
LOC100506012;
19:46999055
cg03969996
79829

PNMAL2

−0.106
BEX5
X:101411275
cg03993934
80323

−0.106

15:98196333
cg11023328
208285

−0.105
ZIC5
13:100605441
cg10523198
199939

−0.105
TIGIT
3:114009756
cg05943254
117166

−0.105
CTNND2
5:11589049
cg17415451
318667

−0.105
MGC27382
1:78693899
cg22559013
398527

−0.105
DLC1
8:13372483
cg08768218
169300

−0.105
F10; F7
13:113783990
cg25796986
450780

−0.105
SOX2-OT
3:181417613
cg06283493
123126

−0.105

13:54898133
cg18817396
341362

−0.105
KIAA1143; KIF15
3:44802566
cg17546649
320901

−0.105
CRYAA
21:44593708
cg21895314
388915

−0.105
FOXS1
20:30437731
cg05366561
106738

−0.105
FIBIN
11:27015592
cg02565993
52210

−0.105
CLC
19:40228820
cg04764056
95048

−0.105

15:84974881
cg06813100
132909

−0.105
FBXO47
17:37123767
cg10600889
201304

−0.105
C14orf23; FOXG1
14:29240992
cg03472898
70248

−0.105
STK10
5:171541827
cg11334870
213456

−0.105
HLA-
6:33041697
cg00798281
16870

DPA1; HLA-

DPB1

−0.105
P2RX5
17:3598755
cg13375828
246413

−0.105
LOC100506012;
19:46998383
cg06484000
126528

PNMAL2

−0.105
CMBL
5:10308785
cg26878318
468990

−0.105
MYO7A
11:76903134
cg24852442
435899

−0.105
DKFZp434L192
7:56555482
cg21720373
386268

−0.105

22:50482250
cg10146330
193299

−0.105
PKD1L2
16:81254209
cg07091758
138538

−0.104

2:75136334
cg12269972
229112

−0.104

6:30433749
cg07017214
137090

−0.104
SLC38A4
12:47226005
cg08005660
155507

−0.104
XPNPEP1
10:111683631
cg17201651
315167

−0.104
MYH11
16:15931580
cg03737209
75526

−0.104
FLOT1; TUBB
6:30696029
cg22024120
390747

−0.104

5:170763941
cg26497768
462323

−0.104
KCNK3
2:26916575
cg20955989
374545

−0.104
TRIM31
6:30080230
cg17048834
312621

−0.104
ABCA7; HMHA1
19:1064938
cg26576206
463804

−0.104
PRKCB
16:23850404
cg26562691
463553

−0.104
GAPDHS; LOC100506469;
19:36024313
cg25681177
449001

SBSN

−0.104
CDSN; PSORS1C1;
6:31096204
cg03880216
78131

PSORS1C2

−0.104
MORC2; MORC2-
22:31316184
cg26278151
458506

AS1

−0.104
PCDHB5
5:140515736
cg15120855
280719

−0.104

6:68849256
cg09531389
182666

−0.104
WNT10A
2:219763642
cg16582803
304901

−0.104

14:56471704
cg05314124
105693

−0.104
MMRN2; SNCG
10:88717623
cg07436701
145067

−0.104

1:31280493
cg25204088
441555

−0.104
RFTN2
2:198540621
cg08373610
162365

−0.104
C1QTNF8
16:1152474
cg04004158
80525

−0.104
LOC100507463;
6:32805692
cg26685246
465648

PSMB8; TAP1;

TAP2

−0.104
THOC2
X:122867073
cg08100265
157187

−0.104
PDLIM4
5:131589552
cg14815361
275561

−0.103
HHATL; KBTBD5
3:42727489
cg25129124
440393

−0.103
LOC84931
2:121223847
cg21406402
381501

−0.103
MACROD2
20:15177509
cg09937190
189621

−0.103
FAM163A
1:179713828
cg24460126
429325

−0.103
LOC100506012;
19:46988034
cg14128773
262082

PNMAL2

−0.103
ABHD8; DDA1;
19:17420304
cg10664184
202380

MRPL34

−0.103
SLC9A3
5:501938
cg22572362
398700

−0.103
C1QTNF8; LOC146336;
16:1133074
cg03327829
67387

SSTR5

−0.103
HCN4
15:73639105
cg11831431
221705

−0.103

3:27638612
cg14143723
262354

−0.103
BST2
19:17516712
cg01329005
27706

−0.103

4:115649889
cg14855679
276322

−0.103
TMEM136
11:120187999
cg09120934
175365

−0.103
IRS4
X:107980846
cg21111568
376933

−0.103

7:55072042
cg13490352
248855

−0.103
NCKAP5
2:134326172
cg18984282
343881

−0.103
NCR1
19:55417496
cg17804112
324505

−0.103
FHL3; SF3A3
1:38461687
cg17077180
313040

−0.102
SEMA5B
3:122712224
cg04830808
96325

−0.102
SLCO1B1
12:21324585
cg04579507
91754

−0.102

22:39323204
cg07123855
139180

−0.102

5:134881662
cg12613020
234541

−0.102

2:220352476
cg20456243
367005

−0.102
BAI1
8:143581070
cg25473866
445797

−0.102
PCDHB17; PCDHB6
5:140528785
cg26866168
468766

−0.102
GABBR2
9:101192792
cg14523238
270180

−0.102

5:74908170
cg00601450
12858

−0.102
OCA2
15:28053339
cg24943998
437498

−0.102
DPF1
19:38721070
cg23480284
413571

−0.102
TRAPPC12; TSSC1
2:3383257
cg12447832
231782

−0.102
FGF8; NPM3
10:103532798
cg16079364
296042

−0.102
CHRND; PRSS56
2:233384489
cg25571880
447246

−0.102
APCDD1
18:10456115
cg14623989
272309

−0.102

X:119151476
cg22956922
404868

−0.102

5:88991074
cg04117076
82698

−0.102

2:131010522
cg13302869
245147

−0.102

13:19243756
cg08628006
166844

−0.102
GCM2; SYCP2L
6:10881782
cg18187244
331085

−0.102

7:158243632
cg23859303
419493

−0.102
C16orf91; CCDC154
16:1478718
cg09615056
184112

−0.102
LRRC10B; MIR4488;
11:61273282
cg15263021
282930

SYT7

−0.102
FBXO7
22:32870150
cg21023126
375623

−0.102

13:112985463
cg17655970
322387

−0.102

15:74060182
cg26579616
463866

−0.102

6:28781594
cg00176718
3961

−0.102
PLK5
19:1542897
cg00392196
8275

−0.102

6:156983315
cg00269725
5770

−0.102
LOC100506776
7:38403507
cg05460050
108373

−0.102

5:15385947
cg00105403
2447

−0.102
CKMT1A
15:43984922
cg26247942
457947

−0.102

1:14462810
cg16164607
297377

−0.102
CDH22
20:44838981
cg07296387
142575

−0.102

10:133156015
cg09005971
173513

−0.101
CHRDL1
X:110038954
cg07653640
149177

−0.101

6:79339334
cg11074783
209107

−0.101
C1orf159
1:1052600
cg10126324
192906

−0.101
RINL; SIRT2
19:39360313
cg02711397
55211

−0.101
ZFP41
8:144339106
cg19504605
351705

−0.101

16:85981336
cg10274029
195601

−0.101

11:2212225
cg08241307
159919

−0.101

15:98196022
cg00744413
15733

−0.101

5:9119047
cg17608082
321764

−0.101
DPYSL5
2:27068081
cg08806184
169893

−0.101
GP6
19:55526208
cg27154418
473807

−0.101
C16orf61; CENPN
16:81039227
cg08265926
160397

−0.101
LOC100129620;
1:99471295
cg03593336
72666

LPPR5

−0.101
HLA-
6:33040610
cg20617328
369385

DPA1; HLA-

DPB1

−0.101
CD3EAP; ERCC1;
19:45901453
cg08884571
369385

PPP1R13L

−0.101
NALCN
13:102060580
cg22191606
393258

−0.101
MGLL
3:127473936
cg15694422
289708

−0.101

2:121279886
cg23405152
412432

−0.101
DNAH17; PGS1
17:76417995
cg22290140
394680

−0.101
PALM2; PALM2-
9:112593847
cg13893012
257062

AKAP2

−0.101
CHAT; SLC18A3
10:50816262
cg04730768
94454

−0.101
CCBL2; RBMXL1
1:89459658
cg23627354
415857

−0.101

21:10888524
cg19433175
350575

−0.101
WDSUB1
2:160142643
cg00168785
3783

−0.101
CYP26B1
2:72357937
cg15160709
281412

−0.101

6:74965323
cg11654562
218523

−0.101
AAAS; SP7
12:53715148
cg23032316
406156

−0.101
ZNF718
4:124693
cg15792688
291287

−0.101

11:120387302
cg06995068
136607

−0.101

7:147500722
cg17372101
317966

−0.101

2:3044737
cg11902863
222986

−0.101

14:77519601
cg13576669
250680

−0.101
PDE11A
2:178770927
cg04628174
92633

−0.101
CCDC64B; HCFC1R1; THOC6;
16:3079708
cg07868599
153015

TNFRSF12A

−0.101
HLA-
6:33044510
cg00750366
15857

DPA1; HLA-

DPB1

−0.101
ZNF767
7:149323101
cg08744726
168908

−0.100
LOC100506012;
19:46999224
cg11410682
214729

PNMAL2

−0.100
SDC3
1:31368797
cg00658151
13923

−0.100
CILP2; NDUFA13;
19:19643534
cg09935271
189575

YJEFN3

−0.100
HOXD3; LOC401022
2:177028804
cg10304824
196084

−0.100
PCDHGA1; PCDHGA10; PCDHGA11; PCDHGA12; PCDHGA2;
5:140807225
cg21929183
389472

PCDHGA3;

PCDHGA4;

PCDHGA5;

PCDHGA6;

PCDHGA7;

PCDHGA8; PCDHGA9;

PCDHGB1;

PCDHGB2;

PCDHGB3;

PCDHGB4;

PCDHGB5;

PCDHGB6; PCDHGB7;

PCDHGB8P

−0.100
SCN7A
2:167350889
cg06038864
118973

−0.100
CEBPZ; LOC100505876;
2:37424015
cg23687288
417012

SULT6B1

−0.100

15:101389354
cg25878441
451879

0.100

20:690915
cg12338552
230066

0.100
KIRREL3-
11:126873181
cg08668551
167552

AS3

0.100
MLNR
13:49795541
cg06476591
126402

0.100
ZNF542
19:56879662
cg03146949
63935

0.100
KY
3:134369987
cg12307306
229684

0.100
TMEM200B
1:29449356
cg00866556
18256

0.100
ERICH1
8:687384
cg01200640
25242

0.100
HOXA5; HOXA6;
7:27187372
cg04265576
85698

HOXA7; LOC100133311

0.100
LOC386758; ZNF582
19:56904901
cg09568464
183339

0.100
ISM1
20:13200973
cg06262436
122823

0.100

10:100109635
cg23078268
407013

0.100
AQPEP
5:115298720
cg25044651
439130

0.100
AJAP1
1:4714672
cg12475759
232236

0.100

15:78112847
cg09369863
179831

0.100
HOXC4
12:54441509
cg10366797
197193

0.100
C7orf50; CYP2W1
7:1029594
cg22505411
397678

0.100
SLC22A3
6:160769116
cg07883823
153297

0.100
CDH8
16:62070086
cg06831576
133330

0.100
CCDC164; EPT1
2:26625047
cg13255216
244382

0.100
GHSR
3:172167445
cg04851268
96789

0.100

2:213402433
cg08042975
156156

0.100
TCHH
1:152081002
cg05523911
109583

0.100
ERBB2
17:37856378
cg26111030
455565

0.100

9:13278626
cg14655855
272946

0.100
EPGN; MTHFD2L
4:75174080
cg07643762
149031

0.100
ISL2; SCAPER
15:76634887
cg02245004
45800

0.100
UGGT2
13:96705123
cg08797194
169739

0.100
TBL1XR1
3:176827739
cg22160300
392814

0.100
LMO3
12:16762831
cg05355757
106496

0.101

17:25676440
cg07143451
139627

0.101
MYF5; MYF6
12:81110706
cg14067873
260821

0.101
EVX2; HOXD13
2:176948693
cg01749491
35793

0.101
OR7G3
19:9238958
cg03494634
70624

0.101
PON2; PON3
7:95025905
cg15927196
293537

0.101
TP73; WRAP73
1:3567986
cg24073122
423203

0.101

1:148854572
cg11818631
221440

0.101
ASCL2
11:2292000
cg13930892
257925

0.101
CNGB1
16:57915850
cg07029201
137333

0.101
HTR4
5:148033708
cg12825070
237836

0.101
C1orf201; NIPAL3
1:24741723
cg21298759
380184

0.101

7:158286570
cg23618588
415687

0.101

5:4942612
cg11468819
215620

0.101

5:56595244
cg19985056
359969

0.101
FLJ23152
6:17102678
cg05312353
105662

0.101
TCHH
1:152080543
cg04938315
98550

0.101
DCC
18:49868477
cg01839464
37773

0.101
FAM155A
13:108519752
cg06446668
125897

0.101
LOC285548;
4:13546151
cg27438798
478567

NKX3-2

0.101

6:29818300
cg22473097
397165

0.101
PSKH2
8:87082023
cg20982735
375026

0.101
UTP14A
X:129065551
cg02699127
54944

0.101
FAM169A
5:74161231
cg07222505
141302

0.101
PLS1
3:142314493
cg00063773
1512

0.101
RUNX1T1
8:93115504
cg01806520
37028

0.101

2:133106819
cg12792250
237266

0.101
LOC654342
2:91848218
cg24829460
435500

0.101

5:2915236
cg21081803
376494

0.101
THRB
3:24536252
cg02333852
47654

0.101
SNAP91
6:84418789
cg16334314
300384

0.101
SGK1
6:134497247
cg03400131
68781

0.101
LOC729852;
7:7726202
cg26804611
467608

RPA3

0.101
ILF2; NPR1
1:153651568
cg04484579
89880

0.101
LOC643714; TOX3
16:52581551
cg02709321
55162

0.101
EYA4
6:133562475
cg20787173
372221

0.101
DBNDD2; PIGT
20:44035850
cg03172947
64447

0.101
PAK3
X:110187421
cg06455967
126034

0.101
HCN1
5:45695922
cg06498267
126802

0.101
ZIC4
3:147111120
cg27606499
481395

0.101
MAGI2-AS3
7:79082531
cg14592474
271684

0.101
WTIP
19:34972358
cg11869770
222476

0.101
UCP1
4:141490153
cg19346645
349167

0.101
COL23A1
5:178017853
cg26996818
471137

0.101
ZC3H12C
11:109964976
cg11758932
220367

0.101
SYT9
11:7273498
cg08185661
158874

0.101

8:41004167
cg09091657
174922

0.101

14:28733613
cg01840183
37791

0.101
CDK6
7:92442568
cg05278074
104986

0.101
FLJ42875; PRDM16
1:2990490
cg17001566
311833

0.102

7:53286906
cg10502121
199449

0.102
IQGAP3; TTC24
1:156542103
cg12262564
229022

0.102
DEAF1; DRD4
11:640606
cg20411756
366324

0.102

12:29303160
cg23787937
418459

0.102
FOXF1; LOC400550
16:86548895
cg08589354
166151

0.102

18:44787492
cg18074954
329008

0.102
KANK3
19:8398300
cg17490089
319937

0.102
PRDM12
9:133534961
cg13465477
248295

0.102
GLRA1
5:151304817
cg25352328
443801

0.102
GRIA2
4:158141570
cg00699993
14796

0.102
ADNP2; LOC100130522;
18:77905119
cg18973878
343754

PARD6G

0.102
TBL1X
X:9432900
cg10839723
205305

0.102
LOC255480; TBX5
12:114845868
cg21907579
389107

0.102
TDRD5
1:179555658
cg17138852
314056

0.102
GPR176
15:40212781
cg17497271
320059

0.102
CHST3
10:73724697
cg19731268
355545

0.102
SNAP91
6:84418659
cg15950068
293877

0.102
PDXK
21:45147292
cg02253535
45973

0.102

5:168728149
cg15927720
293550

0.102
PRDM13
6:100061111
cg17302155
316788

0.102
DLL4
15:41219238
cg16069079
295915

0.102
PDGFRA
4:55100025
cg24799620
435038

0.102
FAM190A
4:91049007
cg17275700
316281

0.102
FUT9
6:96463959
cg25114913
440174

0.102
MOXD2P; PRSS58
7:141951023
cg12970830
240011

0.102
HPS4; SRRD
22:26875563
cg27087377
472647

0.102

17:25676386
cg05977781
117874

0.102

15:96905554
cg00221709
4765

0.102
RARRES1
3:158450208
cg03269060
66248

0.102
KDR
4:55991701
cg25722465
449597

0.102
SOX17
8:55370579
cg26059468
454690

0.102

14:95330880
cg18939596
343247

0.102
DLC1
8:13134166
cg20536983
368192

0.102

2:44312696
cg08613504
166550

0.102
ESR1
6:152085619
cg17741339
323560

0.102
CPLX2
5:175299035
cg06833732
133382

0.102

21:42218932
cg09880551
188645

0.102
CCDC108; CRYBA2;
2:219858146
cg24374738
427940

FEV; MIR375

0.102
FBXL15; NFKB2;
10:104170217
cg26089160
455163

PSD

0.102
PTPRZ1
7:121513695
cg10948929
206989

0.102

5:87979504
cg12991050
240324

0.102
RNF180
5:63461566
cg16485558
303034

0.102
ZDBF2
2:207140303
cg00410106
8675

0.103
CACNA1B
9:140917413
cg11827453
221623

0.103
CUL4B
X:119694554
cg22267947
394373

0.103
DUOX1; DUOXA1
15:45422054
cg24505618
430070

0.103
RUNX1T1
8:93114294
cg07622493
148653

0.103
GBX2
2:237078733
cg07014673
137017

0.103
HOXD4; MIR10B
2:177014949
cg27160395
473893

0.103
GLRB
4:157997363
cg09688546
185354

0.103
DENND4C
9:19298547
cg19584733
353015

0.103
CASC4
15:44579510
cg00093643
2177

0.103

6:9399379
cg20876760
373416

0.103
GBX2
2:237076171
cg20804191
372465

0.103
LY6H
8:144240945
cg00831710
17537

0.103

6:28853021
cg24867279
436176

0.103
ALKBH7; CLPP
19:6362787
cg16848221
309550

0.103

5:1107837
cg22172143
393020

0.103
ZNF729
19:22469860
cg15413034
285081

0.103
TP73; WRAP73
1:3567412
cg16823083
309243

0.103
KBTBD11
8:1949342
cg25021970
438735

0.103
KLF16
19:1851995
cg11434705
215145

0.103
PEX5L
3:179670323
cg18765712
340436

0.103
NFIX
19:13107252
cg06197482
121707

0.103

2:9235972
cg04575202
91657

0.103
PCDHGA1; PCDHGA2
5:140712459
cg21722795
386305

0.103

1:32237923
cg04878000
97320

0.103

12:130422172
cg01448115
30160

0.103
RBFOX3
17:77454437
cg25258515
442358

0.103
EPB41L3
18:5543945
cg16304950
299805

0.103

13:112759355
cg15415452
285112

0.103
PPYR1
10:47083426
cg02394955
48953

0.103
ANKRD20A8P
2:95522902
cg08721908
168505

0.103
C2orf65
2:74813369
cg02102114
43172

0.103
MIR137; MIR2682
1:98519101
cg09896412
188935

0.103
NR1D1; THRA
17:38255871
cg09161455
176141

0.103
RPTOR
17:78815421
cg02363653
48276

0.103
LOC100505806;
5:9545976
cg11011938
208099

SNORD123

0.103
GRIN2A
16:10051500
cg06880615
134389

0.103

16:85369038
cg05877550
115832

0.103
CAPN1; SPDYC
11:64949878
cg25363789
444004

0.103

4:1407989
cg26860935
468675

0.103
THSD7A
7:11871690
cg26748945
466682

0.103
NEURL; SH3PXD2A
10:105344174
cg16311536
299928

0.103
FREM3
4:144621385
cg04514249
90444

0.103
CRNDE; IRX5
16:54965084
cg02056682
42152

0.104
POLR1B; TTL
2:113298655
cg12937159
239513

0.104
PRKD1
14:30396845
cg08608974
166464

0.104
LAIR1
19:54876795
cg20117742
361985

0.104
CNTNAP2
7:145814152
cg16254309
298913

0.104
CRMP1
4:5894930
cg15448975
285648

0.104
ASIP
20:32857151
cg09775533
186730

0.104
RBFOX1
16:6623787
cg04671611
93373

0.104
PCDHA1; PCDHA2;
5:140207609
cg16987900
311601

PCDHA3;

PCDHA4;

PCDHA5; PCDHA6;

PCDHA7

0.104
TGIF1
18:3452302
cg12899157
238913

0.104
ADRBK2
22:25961523
cg15154002
281307

0.104
FBP1
9:97402452
cg14211930
263861

0.104
GABRG2
5:161494500
cg08566437
165741

0.104
SMAD2
18:45458243
cg03294491
66702

0.104
SHISA6
17:11143830
cg08169394
158589

0.104
ADAMTSL3
15:84322946
cg14230666
264293

0.104
TRIM67
1:231296818
cg08855395
170825

0.104
RBP4
10:95361223
cg25793377
450725

0.104
EDIL3
5:83679941
cg07201620
140856

0.104
C10orf114; MIR1915
10:21789124
cg00580562
12369

0.104
CAMK1G
1:209759145
cg14034757
260152

0.104
NET1
10:5488500
cg14426660
268226

0.104
ACTL6B
7:100253914
cg08572611
165841

0.104
TEKT1
17:6734940
cg20663042
370096

0.104
LOC100271702
12:2030223
cg08621624
166700

0.104
OCRL
X:128674222
cg27633753
481846

0.104
ANKRD53; TEX261
2:71205891
cg18006568
327816

0.104
RAB32
6:146864752
cg23833452
419083

0.104
NCAM1
11:112833773
cg12040830
225223

0.104
C3orf26; FILIP1L
3:99595145
cg22092811
391783

0.104

14:95331232
cg00814780
17210

0.104
LOC100507043
14:96342365
cg01718322
35254

0.104
CPLX1
4:789505
cg12792086
237263

0.104
LINC00327
13:24062873
cg08381620
162504

0.104
OLFM2
19:10024282
cg06911487
135026

0.104
FLJ41350; LBX1
10:102987257
cg12646649
235126

0.104
DUSP27
1:167090974
cg17801546
324462

0.104
PCDHA1; PCDHA10;
5:140346199
cg25500080
446199

PCDHA11;

PCDHA12;

PCDHA13;

PCDHA2; PCDHA3;

PCDHA4;

PCDHA5;

PCDHA6; PCDHA7;

PCDHA8;

PCDHA9;

PCDHAC1; PCDHAC2

0.104
ABCC3; CACNA1G
17:48712370
cg00081975
1883

0.104
ZBTB16
11:113953621
cg20268992
364195

0.104
TMEM179
14:105070864
cg10281977
195739

0.104
ASB10; GBX1
7:150870036
cg12649727
235202

0.105

11:79151811
cg09673208
185113

0.105
CA10
17:50235965
cg22702328
400704

0.105
SOX17
8:55371013
cg08044097
156179

0.105
PIWIL1
12:130822603
cg24838063
435641

0.105
SLC7A14
3:170303721
cg21884231
388773

0.105
GRIN2D; GRWD1
19:48946564
cg04419610
88694

0.105
STK24
13:99218657
cg17176619
314752

0.105
FAM159B
5:63986733
cg14004073
259441

0.105
LOC728723; SNORA47;
5:76373719
cg03163459
64262

ZBED3

0.105
ZNF536
19:30866192
cg03758150
75925

0.105
PCDHA1; PCDHA10;
5:140346394
cg21537235
383480

PCDHA11;

PCDHA12;

PCDHA13;

PCDHA2; PCDHA3;

PCDHA4;

PCDHA5;

PCDHA6; PCDHA7;

PCDHA8;

PCDHA9;

PCDHAC1; PCDHAC2

0.105

11:43569269
cg13201808
243496

0.105
GLDN
15:51634039
cg09495418
182011

0.105
UGGT1
2:128953231
cg11873311
222541

0.105
TBX3
12:115129446
cg10297792
195985

0.105
GPR123
10:134902278
cg07779444
151406

0.105
IRX1
5:3592435
cg19814981
357062

0.105
HOTAIRM1; HOXA1;
7:27142682
cg09871315
188506

HOXA2;

HOXA3

0.105
PLK2
5:57756539
cg07479092
145902

0.105
TBX3
12:115123875
cg18573327
337428

0.105
ACTN2
1:236849994
cg20482698
367438

0.105
LOC388499; LRRC8E
19:7953281
cg27615578
481540

0.105
THRB
3:24536889
cg26146027
456200

0.105
GRIA2
4:158141542
cg10410142
197887

0.105
FN3K; FN3KRP
17:80693076
cg03077331
62673

0.105
OPA3; VASP
19:46032528
cg26958124
470450

0.105
HOXD1; LOC401022
2:177053274
cg03450948
69796

0.105
VWC2
7:49813088
cg01893212
38794

0.105

1:241520331
cg13849378
256225

0.105
DLX6-AS1
7:96622709
cg18502142
336304

0.105

4:180979631
cg12950911
239731

0.105
DNAH8
6:38683221
cg03166753
64319

0.105
NETO1
18:70536461
cg13644317
252077

0.105
FLJ12825; HOXC4
12:54454163
cg04024827
80948

0.105

6:125855124
cg02612397
53198

0.105
TP73; WRAP73
1:3567646
cg07382920
144177

0.105

4:165304540
cg21300373
380200

0.105
PRDM8
4:81118588
cg26299084
458882

0.106
ASIP
20:32857072
cg16655240
306231

0.106
TBX18
6:85474093
cg02106850
43270

0.106
THBD
20:23030250
cg09279949
178245

0.106
HOXD8; LOC100506783
2:177004015
cg18516557
336519

0.106
AQPEP
5:115298704
cg22010052
390518

0.106
WNT3A
1:228248013
cg26841013
468320

0.106
C14orf23; FOXG1
14:29236008
cg02681442
54626

0.106
COL4A1; COL4A2
13:110959428
cg06659727
129920

0.106
LOC100192378;
8:77590322
cg09938511
189649

ZFHX4

0.106
MAGI2-AS3
7:79083753
cg07448060
145248

0.106
CHRDL1
X:110039536
cg00619443
13187

0.106
FAM174B
15:93199037
cg25864024
451730

0.106
CNPY1
7:155301734
cg05944137
117184

0.106
PIGZ
3:196695320
cg23484358
413640

0.106
WNT7B
22:46372742
cg17179568
314808

0.106
TMPRSS3; UBASH3A
21:43824071
cg00134539
3054

0.106
EPHA5; LOC100144602
4:66534218
cg23193365
408770

0.106
DGKI
7:137125473
cg13734282
253993

0.106
UNC5C
4:96470286
cg11723848
219719

0.106

10:35256135
cg16738929
307860

0.106
NRG1
8:32504919
cg14663451
273089

0.106
HOTTIP; HOXA13
7:27246799
cg25720795
449560

0.106
LMF1; SOX8
16:1030619
cg05520409
109522

0.106
CRMP1
4:5894923
cg07963234
154775

0.106
HOTAIR; HOXC12;
12:54349169
cg26931862
469970

HOXC13

0.106
FOXI2
10:129535186
cg25539045
446751

0.106

1:41350014
cg13472192
248463

0.106

6:39740405
cg14173968
262984

0.106

20:690693
cg02217786
45276

0.106
PRSS3
9:33750687
cg14369648
267044

0.106
ZNF362
1:33721234
cg03767970
76126

0.106
FGFR1OP; MIR3939
6:167409842
cg02634327
53695

0.106
PCDH8
13:53419963
cg07847863
152703

0.106
HS6ST3
13:96742421
cg08612100
166526

0.106
ARMS2; HTRA1
10:124220367
cg09576143
183453

0.106

3:64430940
cg11236526
211855

0.106
CHST9
18:24765490
cg21895526
388922

0.106
C14orf132
14:96505722
cg16539629
304057

0.106

5:72596646
cg01050429
22138

0.106

8:61823275
cg06011086
118514

0.106
ST6GAL2
2:107502679
cg19412467
350247

0.106
CHAT; SLC18A3
10:50818299
cg11389172
214354

0.106
SLC6A1
3:11033866
cg00375819
7950

0.107
CLEC2L
7:139208852
cg08832906
170404

0.107
CCDC27; TP73-
1:3663435
cg10634619
201918

AS1

0.107
ZNF90
19:20188803
cg03317517
67181

0.107
GBP1
1:89523325
cg11083157
209272

0.107
OSR2
8:99961874
cg01581084
32753

0.107
KCNA7; NTF4
19:49575475
cg26923490
469807

0.107
ISL1
5:50678925
cg01587896
32872

0.107
NEFH
22:29876945
cg23353952
411659

0.107

7:149744935
cg15058253
279644

0.107
DDX25; HYLS1;
11:125774406
cg19792599
356708

PUS3

0.107
CBWD1; FOXD4
9:113530
cg01237333
25956

0.107
MIR1253
17:2659081
cg08457011
163741

0.107
TAS2R1
5:9623366
cg01984802
40719

0.107
TBX18
6:85474090
cg07028914
137326

0.107
ARL5C; CACNB1
17:37321631
cg20555674
368474

0.107
CNTNAP2
7:145813413
cg05749717
113523

0.107

2:165698949
cg21639287
385195

0.107
DNAJC6
1:65775570
cg26885220
469135

0.107
LILRA2
19:55084269
cg16893868
310220

0.107
CRNDE; IRX5
16:54965100
cg06191898
121610

0.107
PRKAR1B
7:751962
cg12441126
231659

0.107
ARHGEF10;
8:1772116
cg22880677
403671

MIR596

0.107

5:143978290
cg02030403
41637

0.107
CBLN4
20:54579084
cg01729827
35479

0.107
HOXD10; HOXD8;
2:176989349
cg09173768
176359

HOXD9

0.107
MIR196A1
17:46713962
cg13769834
254628

0.107
CRAMP1L
16:1665094
cg06810647
132860

0.107
ANGPT1
8:108511174
cg09443479
181117

0.107
DRD1
5:174871289
cg18190187
331134

0.107

1:227729906
cg11846112
221996

0.107
TGFBI
5:135364556
cg03625177
73315

0.107
TRMT2B
X:100307142
cg11708328
219456

0.107
HOXD4; MIR10B
2:177014966
cg12215739
228288

0.107

X:39548267
cg11712793
219521

0.107
DEAF1; DRD4;
11:637035
cg23501406
413927

SCT

0.107
ZNF578
19:52956683
cg14582763
271490

0.107
KITLG
12:88974161
cg25741452
449928

0.107
BIRC5; TMEM235
17:76228233
cg09473315
181656

0.107
DMRTA2
1:50884480
cg10512745
199703

0.107
TMEM132C
12:128752040
cg04475027
89694

0.107
INPP5A; NKX6-2
10:134600675
cg15304699
283459

0.107
FGF8; MGEA5;
10:103536342
cg25209842
441648

NPM3

0.108
SLC22A20
11:64993335
cg23930334
420666

0.108
DIP2C
10:601816
cg06279296
123066

0.108
PRKD1
14:30396515
cg01588388
32879

0.108
EYA4
6:133562332
cg01328892
27704

0.108
PTPRM
18:7566781
cg16474170
302867

0.108
FAM129C
19:17650009
cg12585966
234024

0.108
CD247
1:167409054
cg06900257
134801

0.108
DRD5
4:9783206
cg04597433
92065

0.108
ISCA2; LTBP2
14:74959018
cg26195881
457091

0.108
HOXC4; HOXC5;
12:54408091
cg14569644
271205

HOXC6; HOXC8

0.108
FAM5C
1:190447290
cg23010538
405785

0.108
LRP12
8:105601696
cg00662122
14007

0.108
SFRP1
8:41166990
cg24319902
427005

0.108

13:24270087
cg10885151
205995

0.108
SVEP1
9:113341525
cg13606569
251311

0.108

3:181444563
cg04859466
96950

0.108
GABRA2
4:46391392
cg25145765
440699

0.108
KLF16
19:1851882
cg13382072
246526

0.108
CATSPER2P1;
15:44035561
cg15437748
285428

PDIA3

0.108
TRAF3IP2; TRAF3IP2-
6:111926749
cg15772366
291005

AS1

0.108
PCDHA1; PCDHA10;
5:140345966
cg04454086
89312

PCDHA11;

PCDHA12;

PCDHA13;

PCDHA2; PCDHA3;

PCDHA4;

PCDHA5;

PCDHA6; PCDHA7;

PCDHA8;

PCDHA9;

PCDHAC1; PCDHAC2

0.108
VWC2
7:49813486
cg18206027
331413

0.108

6:157264715
cg16455339
302565

0.108
FAM110C
2:46465
cg14255256
264798

0.108
ZNF148
3:125076480
cg22895305
403903

0.108
ADAMTS16
5:5139874
cg16508480
303412

0.108
LOC100506757;
X:133678716
cg19112977
345819

MGC16121;

MIR424; MIR450A1;

MIR450A2;

MIR450B;

MIR503; MIR542

0.108
SNX9
6:158243833
cg26845300
468408

0.108
TMEM181
6:158957433
cg00590036
12606

0.108

3:75661206
cg24573207
431170

0.108
PSKH2
8:87082014
cg04470072
89611

0.108
C10orf140; MLLT10
10:21814313
cg03891590
78352

0.108
MIR1258; ZNF385B
2:180726035
cg24575676
431204

0.108
UBD
6:29521501
cg20723129
371254

0.108

13:112759386
cg21054521
376149

0.108
NTNG2
9:135118406
cg14408447
267814

0.108
PTPRT
20:41818356
cg13168820
242965

0.109
SOX1
13:112722333
cg15466862
285977

0.109
RSPO1
1:38100467
cg13448605
247923

0.109
FGF8; MGEA5;
10:103536348
cg06169131
121199

NPM3

0.109
HOXB2; HOXB3
17:46618919
cg21780393
387140

0.109
SYT7
11:61335254
cg03200166
64948

0.109
SPATA18
4:52918471
cg17031543
312329

0.109
C3orf25; MBD4
3:129147397
cg17468185
319549

0.109
SRCIN1
17:36718549
cg20090283
361564

0.109
LOC400657
18:72263688
cg20276402
364322

0.109
C14orf23; FOXG1
14:29237480
cg16804284
308960

0.109
GABRG2
5:161494515
cg09220361
177083

0.109

8:72468820
cg24809973
435221

0.109

7:87974722
cg27221053
474880

0.109
NXPH2
2:139537745
cg10989763
207734

0.109
SGPL1
10:72594465
cg09140723
175742

0.109
FGF18
5:170848123
cg01392179
28917

0.109
ZNF300
5:150284796
cg21228005
379112

0.109
ZNF329; ZSCAN18
19:58629828
cg03145999
63909

0.109
LOC255480
12:114852091
cg01184975
24931

0.109
LPHN3
4:62383028
cg16225703
298417

0.109

7:156409058
cg16771407
308382

0.109
UNCX
7:1271236
cg18629009
338270

0.109

6:28945500
cg24126967
424128

0.109
MSX1
4:4860061
cg15092343
280260

0.109
SOX1
13:112721789
cg02547394
51873

0.109
CHST8
19:34112991
cg19594305
353222

0.109
BMP4
14:54413548
cg27302539
476206

0.109
FUT9
6:96463902
cg01758512
35982

0.109

2:240153778
cg25746499
450027

0.109
CCDC50; UTS2D
3:191047240
cg25235397
442049

0.109
PAX1
20:21686282
cg08448701
163575

0.110
UBQLN2
X:56589768
cg02587153
52704

0.110

10:13425015
cg18675735
338977

0.110

18:6414958
cg22058122
391310

0.110
CSMD1
8:4852036
cg12258042
228965

0.110
ASPG; MIR203;
14:104583067
cg23960324
421202

MIR3545

0.110
RACGAP1
12:50426901
cg19796532
356768

0.110

13:20875915
cg14472366
269103

0.110

14:95330984
cg19453488
350906

0.110
ZNF385D
3:21792857
cg26077378
454997

0.110
MBNL2
13:98002933
cg03372334
68296

0.110
ENO4
10:118608698
cg01035689
21828

0.110
CRHBP
5:76249502
cg04306063
86503

0.110
ODZ1
X:124097806
cg24761295
434425

0.110

6:78359965
cg10264012
195459

0.110

7:4921827
cg04816699
96082

0.110
MDGA1
6:37616598
cg03062252
62373

0.110
GJD2
15:35046760
cg21053529
376133

0.110
RLF; TMCO2;
1:40714009
cg06776907
132164

ZMPSTE24

0.110
HS3ST6
16:1968232
cg14936269
277598

0.110
DKFZp434J0226
19:46713473
cg21629821
385058

0.110
ANO1
11:69934109
cg05846633
115247

0.110
KIAA1755
20:36889364
cg14003035
259413

0.110
CORIN; NFXL1
4:47840011
cg26018901
454082

0.110
GLT1D1
12:129337897
cg04054313
81425

0.110

9:13279482
cg06202228
121794

0.110
CADM1
11:115069145
cg05125455
102021

0.110
DPYS
8:105479058
cg10303487
196069

0.110
KDM2B
12:122019080
cg17452615
319270

0.110
FOXI2
10:129535509
cg09614415
184092

0.110
ARHGEF4
2:131673894
cg12910906
239117

0.110
CPNE7
16:89654085
cg10499753
199387

0.110
CBLN1
16:49315302
cg08464190
163914

0.110
ADAM33; ATRN;
20:3641641
cg25164624
440992

GFRA4

0.110
LIMK2
22:31644160
cg15504662
286549

0.110
FLT3
13:28673762
cg26472910
461940

0.110
BANK1
4:102712397
cg14855874
276324

0.110

12:34500585
cg19457237
350958

0.110
KDM2B
12:122018897
cg09151742
175965

0.111

2:130763641
cg08857994
170896

0.111
PAX6
11:31819380
cg26029734
454240

0.111
HMGCLL1
6:55443868
cg06401021
125152

0.111
ZNF578
19:52956832
cg25763393
450297

0.111
TRPC4
13:38444134
cg15696906
289754

0.111
PLEKHA6
1:204256846
cg25407979
444757

0.111
C5orf38; IRX2
5:2743601
cg26195356
457077

0.111
EP400; PUS1
12:132433838
cg26147845
456245

0.111
MLLT3
9:20339790
cg21222426
379016

0.111
CTTNBP2
7:117513348
cg17112089
313639

0.111
EFHD1
2:233499460
cg06842071
133579

0.111
TMEM131
2:98613076
cg02995664
61036

0.111
DLX5; DLX6; DLX6-
7:96647021
cg23262036
410160

AS1

0.111
RAX
18:56940333
cg06676637
130191

0.111
COLEC12
18:500979
cg19461621
351026

0.111
MIR618
12:81331486
cg23441441
412989

0.111

7:64407743
cg24002887
421987

0.111
ST6GALNAC5
1:77334045
cg23243867
409762

0.111
MIR618
12:81331469
cg17061244
312814

0.111
LAMA1
18:7117680
cg07846220
152681

0.111
LOC100506012;
19:46975062
cg21988244
390260

PNMAL1

0.111
FGF12
3:192127330
cg16376000
301109

0.111

4:85403915
cg25174438
441100

0.111
GALR1
18:74961968
cg20872937
373368

0.111
LRIT1; RGR
10:86001254
cg14034858
260156

0.111
LAG3; PTMS
12:6888035
cg11429292
215067

0.111
PDE1C
7:32110523
cg14604568
271937

0.111
ZNF503; ZNF503-
10:77156218
cg20659435
370034

AS2

0.111
CDH8
16:62069337
cg02172312
44501

0.111
ISL1
5:50678913
cg17412886
318628

0.111
THRB
3:24537469
cg08123277
157665

0.111
HOXD10; HOXD11;
2:176972068
cg05500840
109127

HOXD12

0.111
ADAMTS16
5:5140003
cg03209854
65125

0.111

2:200524012
cg27211284
474729

0.111
SLC16A2
X:73641955
cg06805513
132754

0.111
HOXC4; HOXC5;
12:54424964
cg10005224
190710

HOXC6; MIR615

0.111
PTPRZ1
7:121513058
cg05931096
116896

0.111
SOX17
8:55370434
cg15186181
281779

0.112
ZNF536
19:30866194
cg06000994
118339

0.112

1:17199104
cg20168927
362799

0.112
STAC2
17:37381475
cg14328457
266291

0.112
CLMP
11:123008408
cg12995113
240381

0.112
CADPS
3:62860224
cg13514230
249338

0.112
TAPBPL; VAMP1
12:6572482
cg22129323
392333

0.112

13:112849184
cg20681688
370443

0.112
OR51A2; OR51A4
11:4977924
cg07589078
148007

0.112

11:110627909
cg04297660
86337

0.112
DNMT3A
2:25474327
cg10749994
203678

0.112

19:23185714
cg24911113
436942

0.112
CCT8L2; TPTEP1
22:17083482
cg00816224
17246

0.112
SLC35F3
1:234040781
cg09424759
180776

0.112
EPHB2; MIR4684
1:23038177
cg27573841
480859

0.112
HOXC8; HOXC9
12:54398518
cg08254359
160184

0.112
PRDM8
4:81118794
cg06307913
123528

0.112

22:33454324
cg05206884
103569

0.112
CR1L
1:207842927
cg20264068
364122

0.112
DNAAF2; LRR1;
14:50085410
cg24149364
424560

MGAT2; RPL36AL

0.112
MAPK14
6:36076933
cg20559215
368537

0.112
ISL2
15:76630209
cg23513966
414134

0.112
F10; PROZ
13:113807384
cg10067723
191777

0.112
C1orf229; ZNF124;
1:247275344
cg23695504
417170

ZNF669

0.112
HOOK1
1:60280809
cg23996071
421845

0.112
ZNF83
19:53142304
cg17132967
313971

0.112
TACR1
2:75292272
cg14054283
260559

0.112

15:29862568
cg13942157
258175

0.112

4:165305050
cg10453719
198622

0.112
SPAG6
10:22634218
cg12377139
230587

0.112
GRM6
5:178422071
cg23003783
405665

0.112
AQP12A; AQP12B
2:241623436
cg08049592
156267

0.112

16:15219673
cg04381865
87943

0.112
KIAA0182
16:85648263
cg07301329
142673

0.112
HOXC4; HOXC5;
12:54413384
cg15772924
291010

HOXC6; HOXC8

0.112
TCF15
20:591083
cg25984671
453527

0.112
C5orf38; IRX2
5:2751550
cg18371475
334040

0.113
ST6GAL2
2:107503672
cg21649258
385387

0.113
PTPRT
20:41818574
cg27625055
481684

0.113
PRKCG
19:54402455
cg02849693
57883

0.113

8:41754181
cg17331296
317296

0.113
SOX11
2:5836231
cg18897632
342660

0.113

17:55213656
cg11030264
208410

0.113
DPP6
7:153584597
cg14523847
270200

0.113
NLRP14; ZNF214
11:7041549
cg22867063
403403

0.113

6:28921805
cg22489957
397412

0.113
AMPD3; MIR4485;
11:10531596
cg18489034
336073

MTRNR2L8;

RNF141

0.113
PALLD
4:169525923
cg24784416
434791

0.113
KHDRBS2
6:62996119
cg26715952
466174

0.113
PTGER2
14:52780158
cg21502048
382905

0.113
CTNNA2
2:79739863
cg08119884
157578

0.113
PRKAR1B
7:751833
cg00356183
7541

0.113
GPR125
4:22517094
cg08141192
158041

0.113
SLC6A17
1:110693237
cg11885396
222730

0.113
FAT1
4:187645120
cg27475132
479115

0.113
KIAA0748
12:55371892
cg24536818
430655

0.113
TRIM31
6:30071394
cg23642250
416154

0.113
DPP6
7:153584582
cg06495961
126761

0.113

8:142276422
cg25461290
445593

0.113
MRPS15; OSCP1
1:36912487
cg26030770
454254

0.113
EPPK1
8:144952929
cg18153977
330494

0.113

3:184231385
cg15718583
290162

0.113
HAND2; NBLA00301
4:174453166
cg15234400
282488

0.113
EGLN3
14:34420292
cg24665290
432653

0.113
HOXD1; LOC401022
2:177053297
cg19180624
346696

0.113
LINC00472
6:72130209
cg10039188
191305

0.113
DMRTA2
1:50886949
cg25191628
441334

0.113
KIT
4:55524199
cg10087973
192117

0.114

15:87892167
cg02693157
54811

0.114
NXPH1
7:8482235
cg12597389
234250

0.114
CACNG6; CACNG8;
19:54486058
cg02574502
52401

MIR935

0.114
HOXD11; HOXD12;
2:176964720
cg03964958
79739

HOXD13

0.114

7:127910927
cg08234689
159796

0.114
SPAG6
10:22634226
cg18247055
332095

0.114
FAM104B
X:55187561
cg15824287
291790

0.114
FOXQ1
6:1313211
cg26422161
461072

0.114

11:91957992
cg07603330
148311

0.114
UTF1; VENTX
10:135050619
cg25577463
447348

0.114
ARL9; SRP72
4:57371607
cg06922635
135243

0.114
MACROD2; SEL1L2
20:13976143
cg06571075
128176

0.114
CNN3; LOC729970
1:95393096
cg18344652
333645

0.114
DUSP27
1:167090757
cg11236550
211856

0.114
MEGF6
1:3447348
cg17163527
314497

0.114

20:12809929
cg12505343
232775

0.114
CHST8
19:34112683
cg27058486
472166

0.114
PUS1; ULK1
12:132410932
cg24221398
425685

0.114
C14orf23; FOXG1
14:29244278
cg21195256
378436

0.114

1:88928467
cg02664812
54315

0.114
SLC44A2
19:10713016
cg05567294
110272

0.114
LOC100129794
14:37641462
cg25051529
439230

0.114
CRNDE; IRX5
16:54966471
cg16642791
305999

0.114
STAT3; STAT5A
17:40464780
cg25500196
446200

0.114
FGF18
5:170878209
cg02125316
43605

0.114

7:127775630
cg19871348
358070

0.114

7:158380884
cg22282410
394574

0.114

16:1048069
cg11978890
224277

0.114
RGAG4
X:71352048
cg03056321
62257

0.114
ZNF83
19:53142146
cg25793430
450728

0.114
FRYL; SLC10A4;
4:48492304
cg14249348
264663

ZAR1

0.115
HES6; LOC151174;
2:239140182
cg23497383
413854

LOC643387

0.115

6:28911938
cg25005112
438404

0.115
RBFOX1
16:6070188
cg08015447
155664

0.115
CHST8
19:34113214
cg06399302
125117

0.115
PRKG1
10:52752476
cg11175150
210715

0.115
CRNDE; IRX5
16:54965142
cg09641689
184540

0.115
EMX2; EMX2OS
10:119303225
cg15373239
284408

0.115
ATOH1
4:94749865
cg00335712
7088

0.115
DSC3
18:28622474
cg14719951
274021

0.115
IDH1; PIKFYVE
2:209128590
cg06177665
121341

0.115
CAMKK2; P2RX4
12:121678558
cg09297514
178526

0.115
GABRB3
15:27018037
cg18026588
328201

0.115
GNA15
19:3136430
cg01032675
21764

0.115
DPP6
7:153749736
cg18940047
343252

0.115

7:52156489
cg18793404
340916

0.115
KCNK18
10:118976677
cg27455890
478852

0.115
UPK3A
22:45680879
cg07021644
137193

0.115
SLC6A2
16:55689865
cg10362591
197113

0.115

4:104918078
cg05123845
101996

0.115
PON2; PON3
7:95025836
cg08828819
170325

0.115
PROX1
1:214160860
cg17954152
327012

0.115
THRB
3:24536562
cg24120841
424012

0.115
CDK5R2
2:219826870
cg27638196
481940

0.115
TMEM17
2:62732892
cg10848792
205426

0.115
RBFOX1
16:6533163
cg14642432
272661

0.115
PSMD14; TBR1
2:162270993
cg08184652
158859

0.115
FKBP5
6:35654363
cg03546163
71700

0.115
LOC100188947
10:93058376
cg17402294
318468

0.115
KIF26B
1:245820634
cg11424312
214996

0.115
ELAVL4
1:50513766
cg05697849
112668

0.115
KIAA0748
12:55376897
cg25486399
445985

0.115
VAX1
10:118896755
cg11398452
214514

0.115
RFX8
2:102091269
cg12291728
229438

0.115

6:28677112
cg14234426
264370

0.115
MTNR1A
4:187476455
cg25107254
440048

0.115
ID2
2:8817010
cg21946006
389750

0.115
HTR1A
5:63257847
cg09698471
185520

0.115
SORCS3
10:106401319
cg10778841
204179

0.116

14:74100987
cg14527456
270289

0.116
FLRT2
14:85996499
cg01711160
35095

0.116
SHANK1
19:51198381
cg07060551
137922

0.116
ALLC; COLEC11
2:3699195
cg13452994
248021

0.116
GRM6
5:178421711
cg12483476
232367

0.116

3:22413960
cg06062984
119382

0.116
LRRC36; TPPP3;
16:67427339
cg07355841
143680

ZDHHC1

0.116
HOTAIR; HOXC12
12:54355476
cg19188855
346817

0.116
TACSTD2
1:59042275
cg24851854
435890

0.116
NPY2R
4:156130016
cg21512644
383071

0.116
KIRREL3-AS3
11:126873379
cg00373707
7906

0.116
HS6ST3
13:96743087
cg27176138
474164

0.116
UBD
6:29521228
cg15814717
291599

0.116
CBWD2; FOXD4L1
2:114256781
cg10602757
201345

0.116
HES6; LOC151174;
2:239140024
cg13957874
258474

LOC643387

0.116
OPRK1
8:54164296
cg13405783
247011

0.116
NKX2-
14:36992233
cg04224064
84867

1; SFTA3

0.116
CCNA1
13:37005273
cg24297049
426624

0.116

2:91671535
cg02109405
43319

0.116

15:32607923
cg00943360
19827

0.116
PTPRG
3:61547130
cg09472360
181640

0.116
GLRB
4:157998201
cg10146199
193292

0.116
C1orf53; LHX9
1:197875080
cg12578211
233875

0.116
NPTX2
7:98246006
cg08315202
161360

0.116
GDF7
2:20871195
cg10553204
200490

0.116

8:61835848
cg06445016
125876

0.116
PRMT8
12:3600106
cg27316886
476555

0.116
ADAMTS16
5:5139878
cg04136610
83123

0.116
ZNF503; ZNF503-
10:77163383
cg18510056
336418

AS2

0.116

6:28911902
cg13293729
244984

0.116
DMRT1; DMRT3
9:971480
cg07173635
140295

0.116

6:170686343
cg01061164
22368

0.116

5:4942469
cg18101138
329470

0.116
FBN2
5:127874466
cg25532099
446652

0.116
PPM1L
3:160475090
cg04056576
81465

0.116
11-Mar
5:16179210
cg03705912
74857

0.116
SOX11
2:5837057
cg15989068
294511

0.116
INTU
4:128544255
cg16654911
306224

0.116
FAM20C
7:193262
cg08782337
169501

0.116
SLC15A3
11:60719947
cg26980692
470832

0.116
RBFOX1
16:6068835
cg19378133
349684

0.116

14:95826734
cg05162306
102773

0.116
SOX1
13:112717244
cg09469566
181584

0.117
PRPH
12:49689463
cg14029489
260043

0.117
MLXIPL
7:73038859
cg10092878
192247

0.117
ATP4A
19:36048943
cg19715414
355233

0.117
MANEAL; YRDC
1:38261057
cg24433287
428889

0.117
KCNA4
11:30038677
cg15310492
283522

0.117

3:54119792
cg03494612
70623

0.117
MMP17
12:132312461
cg03570417
72216

0.117
ADAT1; KARS
16:75661691
cg01921773
39352

0.117
FIGLA
2:71017541
cg22650617
399823

0.117
CNPY1
7:155324691
cg09090582
174907

0.117
BDNF
11:27740876
cg05733135
113285

0.117
LINC00467
1:211590292
cg20802616
372441

0.117
OXTR
3:8813493
cg08449558
163593

0.117
DNAJB13
11:73668626
cg20737388
371474

0.117
SLC34A2
4:25657365
cg19766441
356236

0.117
LINC00461; MIR9-2
5:87968528
cg14636534
272541

0.117
PIWIL1
12:130822286
cg13861644
256478

0.117
DSC3
18:28622593
cg15439862
285459

0.117
UBD
6:29521046
cg18342026
333604

0.117
GABRA2
4:46391929
cg23160016
408245

0.117
DUSP8; MOB2
11:1575607
cg05280206
105032

0.117
PHACTR2
6:143998958
cg26846959
468429

0.117
FAM47E; SCARB2
4:77134471
cg19050061
344935

0.117
SPG7
16:89600764
cg08905080
171867

0.117
BBX
3:107244746
cg02321062
47394

0.117
ALDH1L1
3:125899370
cg01566526
32429

0.117

3:4856199
cg08998950
173407

0.117
LTBP3
11:65325158
cg08965235
172854

0.118

16:85203635
cg00942219
19808

0.118
PIPOX
17:27369780
cg06144905
120806

0.118
LMNB2
19:2446487
cg18087306
329215

0.118
GUSBP4
6:58263193
cg17976157
327360

0.118
ISL1
5:50679149
cg08734740
168746

0.118
BAALC; C8orf56
8:104153627
cg18168101
330737

0.118

1:65534742
cg20301308
364692

0.118

9:136474735
cg03262554
66122

0.118
ZC3H8
2:113012627
cg27242549
475215

0.118
ZNF148
3:125076233
cg12508343
232821

0.118
MGC45800
4:183064388
cg00053393
1279

0.118
NRG2; PSD2
5:139223811
cg08682153
167769

0.118
HOXA5; HOXA6;
7:27187269
cg06237983
122446

HOXA7; LOC100133311

0.118
CADPS
3:62861055
cg15957055
293976

0.118
KCNQ1DN
11:2891082
cg25203481
441543

0.118
ZFPM2
8:106332119
cg10868817
205750

0.118

3:171543413
cg11639615
218225

0.118
PXDN
2:1748112
cg12164282
227454

0.118
TIGD7; ZNF75A
16:3355553
cg05540369
109851

0.118
SP8
7:20824770
cg27618240
481572

0.118

15:96905729
cg11157253
210450

0.118
ADRA1D
20:4202378
cg04293085
86242

0.118
LOC100130298
8:61880392
cg04882213
97419

0.118
DYNLT1; SYTL3
6:159068210
cg27278961
475791

0.118
PCDHA1; PCDHA2;
5:140201656
cg11781306
220669

PCDHA3;

PCDHA4;

PCDHA5; PCDHA6

0.119
DPP6
7:153584416
cg22620221
399362

0.119
ZNF468
19:53361164
cg08531263
165137

0.119
CNTNAP5
2:124782831
cg08790440
169635

0.119
FBN2
5:127873106
cg17564775
321142

0.119
CDH8
16:62070184
cg01718742
35267

0.119
COX19; CYP2W1
7:1018969
cg01823585
37440

0.119
LPHN2
1:82267931
cg02243785
45777

0.119
LOC100130155;
8:65290484
cg07792478
151647

MIR124-2

0.119
LHX8
1:75595970
cg22694818
400568

0.119
LOC339529; ZNF238
1:244213616
cg19698993
354930

0.119
OLFML2A
9:127531952
cg14046477
260419

0.119
EPHA1; LOC285965
7:143108841
cg16618979
305561

0.119
AZU1; LPPR3;
19:822086
cg21928701
389466

MIR3187

0.119
OSBPL3
7:25005464
cg07110009
138907

0.119

7:52155829
cg11342198
213584

0.119
PREX2
8:68864769
cg06617456
128991

0.119
CHRNA4
20:61992494
cg01743841
35695

0.119
ISLR2; LOC283731
15:74425552
cg01178680
24810

0.119
UNC5D
8:35092823
cg08000065
155421

0.119
PRKAR1B
7:751830
cg27331241
476807

0.119
MAP7
6:136847359
cg18421949
334865

0.119
EPHA6
3:96533511
cg11410023
214721

0.119
HOXA5; HOXA6;
7:27188364
cg19816811
357110

HOXA7; LOC100133311

0.119
PDGFC
4:157892765
cg22451233
396868

0.119
HCG4B
6:29895005
cg01519225
31476

0.119
ATP2C2
16:84402160
cg08974450
173017

0.119

4:187037318
cg05379002
107021

0.119
TRIM71
3:32860178
cg12338417
230063

0.119
POU6F2
7:39125198
cg02367316
48362

0.119
RBP1
3:139258295
cg12497564
232636

0.119
EFS; IL25
14:23834909
cg13011388
240610

0.119
MYRIP
3:39851788
cg07892785
153449

0.119
RAB38
11:87908783
cg01568784
32481

0.119
TBX4
17:59532306
cg14823851
275680

0.119
TOX2
20:42544794
cg03011535
61343

0.120
DLC1
8:13134144
cg03304380
66890

0.120
SNED1
2:241938436
cg08233654
159775

0.120
KIF25
6:168436019
cg12003941
224653

0.120
C1orf35; MRPL55
1:228297864
cg22163199
392875

0.120
CTNNA2
2:79739278
cg18806140
341143

0.120
ALOX5
10:45869702
cg27243389
475225

0.120
NAALAD2
11:89867976
cg21500966
382886

0.120
NLRP2
19:55477755
cg17760849
323892

0.120
AIM1
6:106957995
cg20796467
372352

0.120
ZFPM2
8:106331995
cg15449956
285663

0.120
ISL1
5:50679290
cg11711420
219504

0.120
C3orf15
3:119422161
cg08145590
158129

0.120

4:82965250
cg04643822
92882

0.120
FGFR1
8:38323059
cg13278539
244735

0.120
SRRM4
12:119591747
cg27010159
471336

0.120
UGP2
2:64069682
cg19915305
358803

0.120
GLI4
8:144361073
cg11240062
211921

0.120
TOX2
20:42544792
cg13459498
248157

0.120
AQP4; CHST9-
18:24445692
cg12445775
231741

AS1

0.120
NKX6-1
4:85418265
cg12076463
225925

0.121
PCDHGA12; PCDHGC3;
5:140871385
cg24619378
431928

PCDHGC4;

PCDHGC5

0.121
HOXA10; HOXA10-
7:27204894
cg27009703
471328

HOXA9; HOXA7;

HOXA9; LOC100133311;

MIR196B

0.121
DLG5
10:79622515
cg11063088
208886

0.121
KDM2B
12:122019076
cg15234492
282489

0.121
IRF6
1:209979733
cg21951975
389837

0.121
ACTL6B
7:100254149
cg16024950
295200

0.121
ONECUT2
18:55095177
cg05735180
113314

0.121
WDR17
4:176987020
cg08095852
157102

0.121
CLEC14A
14:38725312
cg08139247
158007

0.121
HOXD4; MIR10B
2:177014555
cg19519747
352000

0.121
UTRN
6:144608500
cg15785898
291201

0.121
MFSD7; MYL5
4:682834
cg24693053
433212

0.121
GABRA5
15:27112430
cg10652393
202197

0.121
PLSCR2
3:146187706
cg02128651
43681

0.121
PENK
8:57358590
cg21694941
385984

0.121
FBN2
5:127873283
cg05209584
103634

0.121
PAX1
20:21686293
cg01783070
36501

0.121

18:6414602
cg08336641
161747

0.121
NRG1
8:31497464
cg24946597
437530

0.121
FBXO39; XAF1
17:6679564
cg02374745
48515

0.121
WNT2
7:116963259
cg07697895
149945

0.121

8:142413013
cg06830360
133304

0.121
SNORA76; SNORD104;
17:62222808
cg20969675
374778

TEX2

0.121
EHBP1; LOC100132215;
2:63275602
cg27344587
477023

OTX1

0.121
IRX1
5:3599686
cg01294808
27051

0.121
CADM2
3:85008587
cg13331200
245621

0.121
FAT1
4:187647690
cg12769506
236972

0.121

10:131762052
cg11757357
220344

0.122
ADAM12
10:128077307
cg05237641
104212

0.122
CLVS2
6:123317569
cg08194879
159033

0.122

12:127940654
cg16065021
295854

0.122
SLC6A3
5:1446208
cg14502484
269687

0.122
ASPG; MIR203;
14:104583071
cg03401997
68837

MIR3545

0.122
CCDC146
7:76747831
cg02901065
58990

0.122
ZFP42
4:188916581
cg15718581
290161

0.122

2:225306901
cg10193763
194181

0.122
HOXD10; HOXD11;
2:176972581
cg24633978
432153

HOXD12

0.122
ENTPD6
20:25177340
cg00926318
19472

0.122
TSHZ1; ZADH2
18:72917387
cg22088248
391726

0.122
POLG
15:89879190
cg24365117
427793

0.122

7:43291318
cg02964324
60381

0.122
NETO1
18:70534298
cg23883696
419843

0.122
POU4F1
13:79170283
cg24221648
425692

0.122
GNAS; GNAS-
20:57427650
cg02890368
58752

AS1

0.122
PDE2A
11:72301724
cg26268145
458304

0.122
ARL9; SRP72
4:57372356
cg14775423
274866

0.122
HLCS
21:38353114
cg22777062
401811

0.122
TP73; WRAP73
1:3568210
cg20677901
370380

0.122

2:190192866
cg25550823
446916

0.122
SNX31
8:101661788
cg10715223
203178

0.122
ARHGEF10; MIR596
8:1771973
cg10964367
207265

0.122
B3GNT4; DIABLO;
12:122688787
cg23445859
413050

LRRC43

0.122
TRPC4
13:38444227
cg16409955
301745

0.122
KCNA1
12:5020693
cg08832227
170388

0.122
EXT2
11:44118094
cg24662154
432585

0.123
ADAMTSL3
15:84363061
cg14598478
271807

0.123
STK32B
4:5053504
cg08323075
161506

0.123
DKFZp434J0226
19:46713446
cg21100328
376752

0.123
RNF180
5:63461803
cg09839635
187877

0.123
CYB561D2; NPRL2;
3:50383175
cg00460268
9723

RASSF1;

TMEM115; ZMYND10

0.123
RNF207; RPL22
1:6269448
cg25286333
442745

0.123

17:2627661
cg12187586
227838

0.123
P2RY12
3:151058783
cg13229867
243994

0.123
DUSP4
8:29210592
cg05128656
102084

0.123
HTR4
5:148034045
cg04091563
82145

0.123
TMEM164
X:109246494
cg04926827
98346

0.123
C1QL1
17:43044660
cg24042242
422692

0.123
PCDHGA1; PCDHGA2
5:140711852
cg05580809
110540

0.123
VSTM5
11:93583693
cg14291919
265581

0.123
ZFP2; ZNF454
5:178367827
cg24843380
435721

0.123
KLHDC10
7:129781152
cg07026433
137279

0.123
SLIT2
4:20257590
cg19940312
359283

0.123
IRF6
1:209979665
cg22029157
390830

0.123

11:71350975
cg13009111
240573

0.123
PITX1
5:134367394
cg23064601
406786

0.123
PLSCR2
3:146187740
cg21569635
384039

0.124
SKAP2
7:26897685
cg03730533
75381

0.124
CABYR; TTC39C
18:21719433
cg26349976
459840

0.124
TSHZ1; ZADH2
18:72916776
cg02750262
56023

0.124
ZNF835
19:57183118
cg08146323
158144

0.124
TBX15
1:119535928
cg24035245
422569

0.124
OSGIN1
16:83986941
cg07978099
155051

0.124
PRKD1
14:30396444
cg10501704
199443

0.124
SCRT2
20:644758
cg12590600
234112

0.124
TRPM4
19:49713828
cg10951975
207052

0.124

5:53564
cg22807585
402379

0.124
DUOX2; DUOXA1;
15:45405103
cg04222582
84830

DUOXA2

0.124

14:99584667
cg23683254
416925

0.124
FEZF1; LOC154860
7:121940216
cg27393010
477821

0.124
NELF; PNPLA7
9:140348828
cg14384158
267359

0.124
PTPN13
4:87515467
cg15543566
287079

0.124
KCTD14; NDUFC2-
11:77734206
cg16769152
308350

KCTD14

0.124
GBX2
2:237076811
cg21426003
381745

0.124
PON2; PON3
7:95025829
cg08520743
164919

0.124
CPEB1
15:83316223
cg27578811
480950

0.124
NTM
11:131780492
cg15617814
288391

0.124
ATP9A
20:50385371
cg01900832
38931

0.124

13:36705475
cg25724283
449620

0.124

10:21462441
cg17426273
318854

0.124
ALX1
12:85674296
cg07780095
151415

0.124

6:106441441
cg03942932
79300

0.125
HECW1
7:43152254
cg08039116
156084

0.125

8:61823027
cg20904475
373766

0.125
PRDM8
4:81118188
cg03463411
70030

0.125
INSR
19:7294093
cg26532951
462966

0.125
HOXD4; MIR10B
2:177014959
cg17104824
313519

0.125
PON2; PON3
7:95025740
cg23230584
409500

0.125
TFAP4
16:4324280
cg00021532
522

0.125
CRNDE; IRX5
16:54965087
cg05870072
115671

0.125

14:103673450
cg26579556
463863

0.125
NXPH2
2:139537824
cg18150439
330428

0.125

13:42002627
cg25532201
446653

0.125
KLHL4
X:86772364
cg15554694
287280

0.125
MALL; NPHP1
2:110873396
cg01615704
33421

0.125
HAAO
2:43020264
cg17246140
315873

0.125
DPP6
7:153584609
cg27032232
471703

0.125
LHFPL4
3:9594385
cg04061117
81564

0.125
EGFL7
9:139551542
cg13900767
257221

0.125
COX16; SYNJ2BP;
14:70827109
cg13099429
241974

SYNJ2BP-

COX16

0.125
LHX6
9:124990456
cg13817952
255647

0.125
KCNK16; KCNK17
6:39281885
cg08315770
161367

0.125
CCT8L2; TPTEP1
22:17082770
cg14505585
269757

0.125
FAM135B
8:139509672
cg23294090
410690

0.125
GDA
9:74764428
cg21170041
377969

0.126
IL1RAPL1
X:28604661
cg06927864
135328

0.126
CIDEA
18:12254551
cg07204280
140912

0.126
NPAS3
14:33403862
cg08117309
157524

0.126
ENPP2
8:120650994
cg02534163
51618

0.126

7:156400711
cg16561657
304460

0.126
STXBP5L
3:120627406
cg05293820
105268

0.126
CNTN1
12:41086680
cg14625113
272330

0.126
IRF6
1:209979283
cg25192855
441351

0.126
CAST
5:96038614
cg24742349
434137

0.126
FBN2
5:127874463
cg11965976
224052

0.126
ATXN2
12:112035212
cg08273772
160571

0.126
PDE4D
5:59189120
cg03323696
67297

0.126
TOX2
20:42544663
cg06779449
132219

0.126
BCOR
X:40005177
cg12737514
236481

0.126
KIAA1530
4:1366597
cg23921777
420508

0.126
CXCL2
4:74965262
cg23244559
409786

0.126
MIR1469; NR2F2
15:96884187
cg07016184
137060

0.126
EGLN2; RAB4B-
19:41319790
cg01282508
26784

EGLN2

0.126
TMEM132C
12:128751460
cg03530754
71358

0.126
PDZRN4
12:41582349
cg21926708
389441

0.126
EFCAB1
8:49647734
cg08258526
160240

0.126
PIN4
X:71401384
cg23905908
420234

0.126
RP11-
1:111813690
cg07197785
140790

165H20.1

0.126
LOC645249
7:156814491
cg00024086
585

0.126
ATHL1; IFITM5;
11:288305
cg08829299
170335

NLRP6

0.126
GALR1
18:74961966
cg03659519
73996

0.126

1:2738746
cg10105681
192507

0.126
RGAG4
X:71351980
cg20347665
365414

0.126
RNF180
5:63461574
cg14591786
271667

0.127
EOMES
3:27772805
cg11642106
218279

0.127
HOXB9; MIR196A1
17:46711017
cg23690166
417069

0.127
ARMC5; TGFB1I1
16:31484032
cg10995380
207836

0.127
PON2; PON3
7:95025855
cg04685170
93636

0.127
PRSS3
9:33749216
cg22410499
396383

0.127
CPNE4
3:131246097
cg08151596
158229

0.127
GABRG3
15:27216529
cg11651237
218458

0.127
B4GALNT2
17:47209827
cg20233029
363633

0.127
MSX1
4:4864488
cg21538208
383498

0.127
ARHGEF4
2:131673771
cg09015973
173696

0.127
PCDHA1; PCDHA10;
5:140261663
cg02051771
42046

PCDHA11;

PCDHA12;

PCDHA13; PCDHA2;

PCDHA3;

PCDHA4;

PCDHA5; PCDHA6;

PCDHA7;

PCDHA8;

PCDHA9

0.127
ASPG; MIR203;
14:104583048
cg13673833
252679

MIR3545

0.127
MAGI2-AS3
7:79083507
cg02523844
51402

0.127
IRX2
5:2739602
cg21573200
384101

0.127
NUP210
3:13431720
cg17336044
317388

0.128

2:132088801
cg14001664
259383

0.128
CCDC130; MRI1
19:13875137
cg14272688
265161

0.128

2:71115370
cg10954469
207096

0.128
ZNF347; ZNF415
19:53635967
cg18301583
332927

0.128
SNED1
2:241938321
cg21384492
381197

0.128
VSTM2A
7:54614477
cg06584494
128412

0.128
MEIS2
15:37388540
cg00691830
14602

0.128
NLRP14; ZNF214
11:7041930
cg17228942
315646

0.128
KCNV1
8:110988043
cg23291534
410667

0.128
MAGI2-AS3
7:79081666
cg06809544
132847

0.128
FBXO39; XAF1
17:6679348
cg00376544
7966

0.128
PTF1A
10:23481176
cg22746058
401390

0.128
TAL1
1:47691160
cg10810752
204761

0.128
FBRSL1
12:133137479
cg03621470
73255

0.128
CCDC36; LOC646498
3:49236946
cg03540175
71588

0.128
CXXC4
4:105412800
cg22604213
399113

0.128
MSX1
4:4864902
cg11078084
209175

0.128
FLJ45983; GATA3
10:8097641
cg17124583
313810

0.128
ADRA1B
5:159343549
cg07011172
136949

0.128
UBD
6:29521272
cg22762215
401614

0.128
TGFBI
5:135364568
cg15146621
281189

0.128
CHST8
19:34112825
cg26565021
463587

0.128
JPH1
8:75234269
cg23599843
415405

0.128
ACSS1
20:25039707
cg03321508
67252

0.128
BASP1; LOC285696
5:17218778
cg14306451
265851

0.128

11:79148502
cg05454619
108297

0.128
NLRP14; ZNF214
11:7041752
cg11838299
221836

0.128

2:9235898
cg20610452
369302

0.129
PCDHA1; PCDHA10;
5:140346236
cg12832313
237924

PCDHA11;

PCDHA12;

PCDHA13; PCDHA2;

PCDHA3;

PCDHA4;

PCDHA5; PCDHA6;

PCDHA7;

PCDHA8;

PCDHA9; PCDHAC1;

PCDHAC2

0.129
C8orf42
8:495736
cg05142982
102391

0.129

11:70962935
cg11263364
212293

0.129
CDH12
5:21751337
cg23404351
412413

0.129
LOC100507055;
12:133195094
cg00058329
1387

P2RX2; POLE

0.129
CCDC164; EPT1
2:26624934
cg14273450
265175

0.129
ISM1
20:13200929
cg22588144
398900

0.129
EGR2
10:64578919
cg22903908
404041

0.129
GSDMD; ZC3H3
8:144626190
cg09422696
180737

0.129
KCNK9
8:140715802
cg21415530
381621

0.129

3:94243571
cg16274205
299307

0.129
UNC80
2:210636539
cg24938830
437420

0.129
CABLES2; RPS21
20:60958108
cg14168305
262866

0.129

11:124324477
cg03252499
65933

0.129
FAT1
4:187645144
cg24410535
428521

0.129
PPP1R14A; SPINT2
19:38747378
cg02571816
52340

0.130
ASIP
20:32856898
cg05267394
104806

0.130
CCDC144A
17:16593885
cg02879122
58511

0.130
CRISPLD1
8:75896720
cg15953602
293925

0.130
KAL1
X:8700172
cg18396832
334461

0.130
CELF1
11:47528955
cg13308137
245225

0.130
HOXC4; HOXC5;
12:54404315
cg13545297
249972

HOXC6; HOXC8;

HOXC9

0.130
DOCK1; FAM196A
10:128994608
cg25984344
453521

0.130
LOC100507266
4:4577273
cg07914772
153870

0.130
KCNS2
8:99440279
cg14486338
269395

0.130

5:3093070
cg20428720
366575

0.130
HOXA10; HOXA10-
7:27204981
cg26521404
462738

HOXA9; HOXA7;

HOXA9; LOC100133311;

MIR196B

0.130
RNF180
5:63461582
cg06776999
132168

0.130
MTRNR2L4; OR2C1
16:3415077
cg09999114
190605

0.130
PENK
8:57358312
cg12877723
238608

0.130
NETO1
18:70534767
cg18448581
335334

0.130
TTC40
10:134650467
cg25403174
444670

0.130
ASXL3
18:31158234
cg24880056
436440

0.130
DEAF1; DRD4;
11:637038
cg15861585
292487

SCT

0.130
GLT1D1
12:129337910
cg06419750
125449

0.130
LOC643714; TOX3
16:52580987
cg26817217
467846

0.131
UNCX
7:1265851
cg15591276
287897

0.131
RARRES1
3:158450251
cg14226182
264214

0.131
PRDM8
4:81118500
cg19409579
350194

0.131
DQX1; PCGF1;
2:74742786
cg19656282
354267

TLX2

0.131
STL
6:125283245
cg24822696
435377

0.131
CPNE4
3:131756545
cg12981577
240178

0.131
UBD
6:29521407
cg03402459
68848

0.131
HLCS
21:38362725
cg14785464
275096

0.131
SHROOM2
X:9753940
cg26318441
459244

0.131
FTSJ2; NUDT1;
7:2289054
cg17467898
319545

SNX8

0.131
PCDHB10; PCDHB16;
5:140562738
cg21081817
376495

PCDHB7;

PCDHB8;

PCDHB9

0.131
NOS1
12:117798954
cg04883903
97454

0.131
CHL1
3:238615
cg07746943
150879

0.131
SGPP2
2:223289277
cg00043095
1074

0.131
TUSC1
9:25678015
cg13985784
259065

0.131
NKX2-8
14:37051417
cg10530851
200070

0.132
FRYL; SLC10A4;
4:48492225
cg22773661
401769

ZAR1

0.132
LOC402160; RNF4
4:2464050
cg21722242
386297

0.132
CHL1
3:239207
cg21145524
377484

0.132

18:73167671
cg12975230
240067

0.132
SALL1
16:51188697
cg00683332
14419

0.132
FAM19A5
22:48972349
cg06273376
122999

0.132
GRM6
5:178422128
cg00582971
12427

0.132
RTBDN
19:12936512
cg07583894
147890

0.132
HOXA10-
7:27192656
cg23263937
410186

HOXA9; HOXA5;

HOXA6; HOXA7;

HOXA9;

LOC100133311

0.132
TMEM45B
11:129685751
cg27274706
475714

0.132
NRK
X:105066526
cg07674139
149532

0.132
NRG1
8:31497829
cg26267340
458285

0.132
NAALAD2
11:89867653
cg01577414
32669

0.132
SMTNL2
17:4488345
cg07888347
153363

0.132
CHRNB1; FGF11;
17:7341641
cg25563256
447126

TMEM102

0.132
NEFM
8:24771326
cg07552803
147256

0.132
HMGCLL1
6:55443757
cg11907729
223067

0.132
WNT2B
1:113051846
cg27181253
474270

0.132
RADIL
7:4869981
cg00469380
9930

0.132
NRXN1
2:50574196
cg14875171
276641

0.133
CTNNA2
2:79740208
cg04670857
93356

0.133
DOCK1; FAM196A
10:128994605
cg12204732
228111

0.133

12:132146956
cg24533007
430572

0.133
CBLN2
18:70209432
cg13478228
248599

0.133
PIEZO2
18:11149470
cg03686593
74481

0.133
NELL1
11:20690957
cg17371081
317950

0.133
SLC34A2
4:25657381
cg03738352
75550

0.133

3:74663796
cg00735667
15563

0.133

5:132947501
cg23236554
409620

0.133
LRRC4C
11:40315392
cg17949440
326949

0.133
CHST9
18:24765485
cg16933181
310893

0.133

6:168147405
cg07147204
139710

0.134
CNTNAP2
7:145813417
cg11592503
217489

0.134
ENTPD2; NPDC1
9:139943146
cg14024893
259944

0.134
MAGI2-AS3
7:79083445
cg04652097
93018

0.134
TACR3
4:104640662
cg18538958
336883

0.134
NXNL2
9:91150537
cg14347199
266666

0.134
COX6B2; FAM71E2;
19:55866087
cg20106459
361820

IL11; SUV420H2

0.134
DPRXP4; RNF135
17:29297391
cg01347228
28034

0.134
GPR6
6:110300573
cg26252167
458027

0.134
MAN1C1
1:25944514
cg10706230
203035

0.135
TJP1
15:30114474
cg19965221
359674

0.135
SSPO
7:149484798
cg16516272
303562

0.135
C3orf25; MBD4
3:129147541
cg14779951
274962

0.135

13:50701501
cg23104954
407495

0.135
LRP3
19:33685817
cg10276227
195631

0.135
HOXD10; HOXD8;
2:176994448
cg14473102
269120

HOXD9;

LOC100506783

0.135
SNAP91
6:84418433
cg24190603
425243

0.135
ISL1
5:50679147
cg16318053
300061

0.135
PCDHA1; PCDHA10;
5:140261653
cg19876814
358160

PCDHA11;

PCDHA12;

PCDHA13; PCDHA2;

PCDHA3;

PCDHA4;

PCDHA5; PCDHA6;

PCDHA7;

PCDHA8;

PCDHA9

0.135
SSTR1
14:38678420
cg18443253
335246

0.136
KCNQ4
1:41248881
cg16294363
299640

0.136
DUSP27
1:167090646
cg17104258
313508

0.136

4:170696239
cg18912209
342859

0.136
CXCL5
4:74864165
cg27109129
473022

0.136
LHX8
1:75602412
cg08146483
158147

0.136
CCR6
6:167559913
cg16338365
300452

0.136
KIF17; SH2D5
1:21044101
cg09793172
187028

0.136
ANKRD26P3;
13:19918586
cg06722407
131065

LINC00421

0.136
ZFP42
4:188916875
cg10242602
195098

0.136
UBD
6:29521430
cg15818307
291669

0.136
HOXD1; LOC401022
2:177053292
cg05099387
101608

0.136
ISM1
20:13200944
cg14060111
260677

0.136
NMBR
6:142409507
cg20747266
371647

0.137

7:1287065
cg12560987
233619

0.137
STL
6:125283953
cg10621825
201643

0.137
FAM181B
11:82444798
cg09617579
184158

0.137
DACH2
X:85402643
cg16259355
299014

0.137

13:21872234
cg11317459
213174

0.137
IRX4
5:1882885
cg14507560
269807

0.137
FGD3
9:95737070
cg14263098
264963

0.137

7:157477846
cg04207084
84494

0.137
AATF; LHX1
17:35300010
cg19760241
356113

0.137
HES6; LOC151174;
2:239149859
cg24127874
424152

LOC643387;

PER2

0.137
HOXD4; MIR10B
2:177014962
cg00014998
368

0.137
C5orf63
5:126409308
cg21113900
376968

0.137
SLC16A11; SLC16A13
17:6946059
cg19639560
354003

0.137
ZBTB44
11:130185651
cg14482569
269324

0.137
ARHGEF4
2:131674140
cg07815799
152125

0.137
DAXX; TAPBP;
6:33280424
cg26083458
455084

ZBTB22

0.137
DPP10; LOC389023
2:115919829
cg01718116
35249

0.137
OR2H1
6:29427519
cg05111645
101800

0.137
HAS1; LINC00085
19:52206667
cg17519645
320492

0.137
TGFBI
5:135364580
cg09873933
188549

0.138
NAALAD2
11:89867637
cg16886581
310118

0.138

14:95331190
cg03459776
69950

0.138
FOXF2
6:1390622
cg12221475
228386

0.138
THRB
3:24537050
cg27526665
479998

0.138

7:156400779
cg18584424
337608

0.138
MIR3663
10:118922493
cg24234899
425848

0.138
PITX1
5:134364387
cg00396667
8373

0.138
DRD5
4:9783198
cg03045635
62021

0.138
SIK3
11:116857794
cg09458566
181396

0.138

13:109147921
cg03994318
80330

0.138
IGF2BP1
17:47075880
cg02745847
55935

0.138
SKINTL
1:48559803
cg08871545
171173

0.138
LMX1A
1:165204796
cg09118258
175320

0.138
GATA6
18:19756877
cg12615165
234584

0.138
CYB561D2; NPRL2;
3:50383079
cg20881888
373460

RASSF1;

TMEM115; ZMYND10

0.138
NXNL1; TMEM221
19:17559217
cg18380550
334165

0.138
C12orf53
12:6818384
cg23877043
419727

0.138
TAL1
1:47691158
cg10380348
197448

0.139
ALPK3
15:85360664
cg20318166
364967

0.139
VSTM2A
7:54614620
cg06139908
120728

0.139

15:26108391
cg03419058
69144

0.139
OPCML
11:132813563
cg18710784
339517

0.139
HOXA5; HOXA6;
7:27187560
cg14044640
260386

HOXA7; LOC100133311

0.139

6:27525678
cg20494374
367603

0.139
KDM1A; MIR3115
1:23361764
cg25002551
438359

0.139
RLF
1:40626599
cg18646240
338570

0.139
NRSN2
20:328035
cg21192095
378373

0.139
MSX1
4:4864430
cg24840099
435675

0.139
FLJ16779; NKAIN4
20:61886079
cg08111446
157414

0.139
DUSP4
8:29210154
cg13635007
251899

0.139
MAGI2-AS3
7:79083509
cg24021956
422308

0.139
H2AFY
5:134735637
cg15613420
288307

0.139
PLD3
19:40871823
cg08360726
162147

0.140
KIRREL3; ST3GAL4
11:126286828
cg12804791
237513

0.140
ASIP
20:32856846
cg16440058
302309

0.140
NKAIN3
8:63161609
cg15858239
292441

0.140
SMAD3
15:67396487
cg19193595
346888

0.140
ALPK3
15:85360655
cg25895948
452116

0.140
C8orf83
8:93977794
cg16560711
304445

0.140
MSX1
4:4864532
cg09748975
186296

0.140
ACTN3; CTSF
11:66326798
cg05475524
108647

0.141
DPP6
7:153584873
cg14564076
271091

0.141
CTNNA2
2:79740185
cg19707040
355066

0.141
SOX1
13:112721325
cg24604013
431705

0.141
DOCK1; FAM196A
10:128994297
cg06525651
127283

0.141
SLC6A18; SLC6A19
5:1222847
cg04248937
85368

0.141
C14orf23; FOXG1
14:29236898
cg07489048
146092

0.141
NANS
9:100819928
cg13527921
249630

0.141

11:44545144
cg13759632
254444

0.141
LRP12
8:105601036
cg24098951
423650

0.141
COL23A1
5:178004091
cg08475953
164148

0.141
ASGR1
17:7077709
cg03975755
79935

0.141

11:133837265
cg23152235
408116

0.141
SIM2
21:38070671
cg26938272
470089

0.141
SCN2B; SCN4B
11:118023765
cg18718634
339649

0.141
FZD5
2:208631684
cg15714846
290094

0.141
DOCK1
10:128593946
cg23665778
416569

0.141
INPP5A; NKX6-2
10:134600701
cg17996619
327663

0.141
ONECUT2
18:55095249
cg15222899
282298

0.141
ZDHHC4
7:6616423
cg19149522
346313

0.141
OR10AD1
12:48592721
cg23748340
417996

0.142
NLRP2
19:55477759
cg19689876
354758

0.142
NXPH2
2:139537845
cg00804628
16987

0.142
FAIM3; IL24
1:207082828
cg06528575
127352

0.142
ZC3H3
8:144599125
cg13071618
241523

0.142
FAM84A
2:14775046
cg05602862
110952

0.142
FAM84A
2:14773973
cg16846645
309527

0.142
HMX3
10:124897048
cg15396686
284826

0.142
RNF207; RPL22
1:6269260
cg15731815
290408

0.142
LOC100188947
10:93058549
cg04285822
86104

0.142
HOOK1
1:60280812
cg15900248
293091

0.142
DRD5
4:9783196
cg23847712
419333

0.142
CNTN4
3:2140256
cg04222358
84827

0.142

3:159818742
cg07617768
148563

0.142
GLRB
4:157997367
cg16269431
299215

0.143

2:68917482
cg18670846
338907

0.143

8:41624841
cg07162571
140077

0.143
MTUS2
13:30055092
cg05122437
101967

0.143
FAM110B
8:59058254
cg13247663
244256

0.143

2:92027943
cg27311294
476418

0.143
TNR
1:175568559
cg24932457
437299

0.143
TNIP3
4:122078348
cg26832294
468154

0.143
C5orf63
5:126409007
cg10200291
194305

0.143
BCOR
X:40012100
cg06548617
127783

0.143

11:32008961
cg20019985
360529

0.143
OCRL
X:128674224
cg05032353
100321

0.143
CHST8
19:34113010
cg16190732
297843

0.143
UBD
6:29520774
cg08065408
156530

0.143
PCDHGA1; PCDHGA10;
5:140787430
cg07613945
148493

PCDHGA2;

PCDHGA3;

PCDHGA4;

PCDHGA5;

PCDHGA6;

PCDHGA7; PCDHGA8;

PCDHGA9;

PCDHGB1;

PCDHGB2;

PCDHGB3;

PCDHGB4;

PCDHGB5; PCDHGB6;

PCDHGB7

0.143
SYT15
10:46970625
cg09373037
179902

0.143
FOXI2
10:129535669
cg07918545
153959

0.144
LOC649133; POU2F3
11:120110882
cg26357587
459979

0.144
CSMD1
8:4849827
cg23495279
413823

0.144
OSTalpha; ZDHHC19
3:195934355
cg26292150
458748

0.144
PITX1
5:134363877
cg04223420
84848

0.144
PDZRN4
12:41582362
cg16896079
310254

0.144
SH2D4B
10:82295864
cg15642854
288829

0.144
UNC80
2:210636560
cg04100532
82347

0.144
CYB561D2; NPRL2;
3:50383118
cg11270070
212403

RASSF1;

TMEM115; ZMYND10

0.144
DPP6
7:153749756
cg15549927
287181

0.144
HCN1
5:45695643
cg18273840
332528

0.144
LHX8
1:75602167
cg08272731
160551

0.145
UBD
6:29521420
cg22305167
394855

0.145
ADAMTS20
12:43945892
cg19619405
353636

0.145
HAGH
16:1863053
cg00935504
19660

0.145
ISM1
20:13200931
cg04432319
88934

0.145
ANKS1B
12:99288805
cg03609960
73052

0.145
LHX3
9:139085579
cg04455058
89330

0.145

6:10382103
cg20906291
373785

0.145
FAM110B
8:59058273
cg12615766
234593

0.145
CYP1A1
15:75018852
cg20004910
360290

0.145
CACNB2
10:18429703
cg02456226
50000

0.145
SNTG2
2:1134065
cg16519574
303633

0.145
DPYS
8:105478855
cg16783744
308581

0.145

19:57618136
cg18384778
334232

0.145

2:200524189
cg20711639
371065

0.145
HLA-
6:33053608
cg01991743
40852

DPA1; HLA-

DPB1

0.146
GNG12; LOC100289178
1:68299409
cg13184736
243235

0.146
NAALAD2
11:89867679
cg18540157
336897

0.146

1:241520286
cg14156405
262603

0.146

18:4455337
cg25627226
448224

0.146
PLSCR2
3:146187126
cg24092307
423558

0.146
MAD2L1BP; RSPH9
6:43612908
cg17536595
320768

0.146
GALNT10
5:153569246
cg13372456
246337

0.146
KCNA4
11:30038675
cg08490115
164399

0.146

7:158380886
cg27392792
477814

0.146
KY
3:134369661
cg24675998
432827

0.146
IRF6
1:209979624
cg09509183
182272

0.147

7:156400881
cg27483342
479249

0.147
ZSCAN1
19:58545333
cg27391267
477779

0.147
NAALAD2
11:89867704
cg21817737
387693

0.147
NID1
1:236228741
cg07157830
139963

0.147
TCHH
1:152079713
cg16689481
306872

0.147
ZBTB44
11:130185670
cg05227350
103986

0.147
AGAP1
2:236412034
cg11045331
208636

0.147
KDM2B
12:122019006
cg07793808
151670

0.147
KIF12
9:116860650
cg14326196
266248

0.148
FAM150A
8:53477881
cg09442654
181101

0.148
ADAP1
7:968552
cg05904016
116371

0.148
DOCK1; FAM196A
10:128994644
cg03129384
63592

0.148
MAML2
11:95969587
cg05270552
104870

0.148
SP8
7:20824932
cg23093589
407294

0.148

12:119212248
cg22125805
392264

0.148
ZSCAN18
19:58609618
cg22721334
401040

0.148
FOSB
19:45976195
cg12542255
233333

0.148
ZSCAN18
19:58609602
cg25784220
450602

0.148
GALR1
18:74962672
cg06360427
124375

0.148

5:168728081
cg07136998
139473

0.148
ANKRD18A; FAM201A
9:38622559
cg21189438
378326

0.148
CSGALNACT2;
10:43633030
cg07178550
140402

RET

0.148

13:53775410
cg13974192
258762

0.149
DIAPH1; PCDHGA12;
5:140892822
cg08860070
170948

PCDHGC3;

PCDHGC4;

PCDHGC5

0.149
DNAAF2; LRR1;
14:50084155
cg22857670
403218

MGAT2; RPL36AL

0.149
MACROD2; SEL1L2
20:13976096
cg01552272
32076

0.149
MYH13
17:10220829
cg13984289
259022

0.149

22:20284604
cg00192046
4240

0.149
CCDC148; PKP4
2:159312727
cg14426788
268232

0.149

1:23544995
cg19743168
355780

0.150
GLRB
4:157997360
cg22065614
391410

0.150

16:51671357
cg07302051
142686

0.150
ZFP42
4:188916943
cg14189571
263343

0.150
UBD
6:29520752
cg11935738
223492

0.150
CPSF3; IAH1
2:9614225
cg08047252
156223

0.150
GP9
3:128787213
cg20264543
364127

0.150
CCR6
6:167559851
cg02524205
51410

0.150
EFCAB1
8:49647809
cg11469098
215629

0.150
IRX4
5:1876397
cg14451382
268670

0.150
ARHGAP23
17:36666642
cg15825321
291821

0.150
CLEC14A
14:38724648
cg16404157
301618

0.150
CACNA2D3
3:54155663
cg18143243
330278

0.151
BTG4; C11orf88;
11:111383624
cg23211240
409137

MIR34B; MIR34C

0.151
GTF3A; MTIF3
13:28016624
cg26772116
467001

0.151

16:49499006
cg01517680
31431

0.151
CTTN
11:70262058
cg16629523
305772

0.151
CCDC106; U2AF2;
19:56159485
cg08496742
164543

ZNF580;

ZNF581

0.152
DQX1; PCGF1;
2:74743009
cg07203423
140895

TLX2

0.152
KCNIP1
5:169960825
cg10931884
206704

0.152
MAL2
8:120220856
cg02225716
45426

0.152
GDF6
8:97173034
cg21859781
388371

0.152
HOXC4; HOXC5;
12:54424203
cg13826247
255805

HOXC6; MIR615

0.152
NCAM1
11:112831501
cg21727486
386364

0.152
ZNF503; ZNF503-
10:77156697
cg25023298
438769

AS2

0.152
MDGA1
6:37616803
cg24442454
429044

0.152
SHROOM2
X:9754927
cg05782106
114103

0.152

4:1515011
cg08480901
164253

0.153
NXPH2
2:139537826
cg14923640
277390

0.153
BDNF
11:27740813
cg13974632
258776

0.153

3:74663689
cg24346629
427487

0.153

4:1400189
cg24496475
429912

0.153

14:97058777
cg11871960
222513

0.154
ATP2C2
16:84402158
cg07507755
146441

0.154

7:32358540
cg27511599
479742

0.154
INTU
4:128544375
cg26114043
455622

0.154
PNLIPRP2
10:118387207
cg18699744
339327

0.154
WIPI2
7:5271480
cg26660312
465112

0.154
GALNTL6
4:172734431
cg22153181
392677

0.154
MSI2
17:55362836
cg07249730
141786

0.154
LIN9; MIXL1
1:226411057
cg18564989
337293

0.154
GPR125
4:22520573
cg13702087
253322

0.155
MMP16
8:89340139
cg12818557
237751

0.155
11-Mar
5:16179660
cg09017434
173718

0.155

5:143978357
cg11527001
216436

0.155
ADAMTS16
5:5140001
cg22954449
404825

0.155
PITX1
5:134365728
cg18606375
337970

0.155

10:109674526
cg00157668
3542

0.155
TSHZ1; ZADH2
18:72916393
cg11568697
217092

0.155

2:240135921
cg18121901
329904

0.155
LYPD1; NCKAP5
2:133427612
cg25571189
447240

0.155
NAALAD2
11:89867809
cg12403137
230998

0.155
HOXC8; HOXC9
12:54396990
cg22679316
400266

0.155
ANKRD36B
2:98206733
cg23224356
409392

0.156
NKAIN3
8:63161589
cg08855288
170823

0.156
RPS7P5
1:240161445
cg21854408
388273

0.156

12:116354837
cg20169823
362815

0.156
GABRA5
15:27112902
cg03462380
70010

0.156
UNCX
7:1267228
cg11715858
219570

0.156
TNIP3
4:122078167
cg10061361
191660

0.156
CDH11
16:65157428
cg07537692
146986

0.156
DNAJB6
7:157192974
cg25039694
439065

0.156
DOCK1; FAM196A
10:128994432
cg03242819
65770

0.156
ADAMTSL1
9:18514052
cg14470762
269062

0.157
CPNE9; MTMR14
3:9745610
cg02741521
55842

0.157
KIF25
6:168436099
cg18319852
333241

0.157
PIN4
X:71401206
cg26578373
463841

0.157
ANKRD36BP2
2:89065379
cg02646394
53977

0.157
PXDN
2:1748132
cg25181651
441181

0.158
GPR78
4:8582227
cg18901644
342716

0.158
ADAMTS16
5:5139797
cg16670809
306536

0.158

18:6414974
cg18556788
337142

0.158
GRM7
3:6903019
cg27199820
474552

0.158
CBWD2; FOXD4L1
2:114261369
cg23850283
419371

0.158
DPP10; LOC389023
2:115919006
cg03753331
75826

0.158
MIR4634
5:174178693
cg12398645
230921

0.159
SEMA3C
7:80548456
cg03823904
77109

0.159
DHRS4L2
14:24476559
cg10926857
206629

0.159
WBSCR17
7:70597058
cg02300154
46944

0.159

11:2367787
cg20805368
372479

0.159
NTM
11:131781257
cg19717586
355276

0.159
FLJ31485; FZD10
12:130647004
cg21885046
388782

0.160
CBLN1
16:49316197
cg03389653
68591

0.160
GBX2
2:237076815
cg19761848
356155

0.160
BCOR
X:40035961
cg00016934
407

0.160
HS3ST2
16:22825046
cg09191731
176695

0.160
ZNF148
3:125076372
cg02970696
60506

0.160
PROZ
13:113819073
cg00898013
18847

0.160

2:130971164
cg08566455
165743

0.160

7:32467657
cg18961681
343589

0.160

7:152621979
cg08202754
159199

0.161
FEZF1; LOC154860
7:121946036
cg10485664
199138

0.161
NKAIN3
8:63161579
cg01906015
39032

0.161
PROCA1; RAB34;
17:27044629
cg21816330
387671

RPL23A;

SNORD42A; SNORD42B;

SNORD4A;

SNORD4B;

TLCD1

0.161
DOCK1
10:128593922
cg06128198
120545

0.161
HTR4
5:148033882
cg11438011
215195

0.161
PITX1
5:134363973
cg07274716
142211

0.161
UHRF1BP1
6:34760872
cg07306190
142760

0.161
IRX4
5:1887300
cg07565505
147521

0.161
SOX17
8:55370429
cg11214140
211422

0.161
GRHL2
8:102505986
cg03650674
73811

0.162
ABCB11; G6PC2
2:169769616
cg05703053
112745

0.162

18:6729810
cg02824202
57399

0.162
GALR1
18:74962000
cg17911318
326333

0.162
KCNA4
11:30038672
cg15044957
279439

0.162
CNTNAP2
7:145813421
cg21126583
377176

0.162
NID1
1:236228744
cg04837025
96465

0.162
THRB
3:24536474
cg20985755
375077

0.162
COBL
7:51384371
cg12988534
240269

0.162
GDF7
2:20870362
cg07755735
151051

0.162
ARHGAP33; C19orf55
19:36265700
cg18805164
341126

0.163

8:143070187
cg06573787
128217

0.163
ERG
21:40033163
cg12884169
238711

0.163
PON2; PON3
7:95025736
cg07121856
139138

0.163
HOXD10; HOXD11;
2:176972563
cg11546137
216732

HOXD12

0.164
NSUN4
1:46814106
cg15580309
287719

0.164
CYB561D2; NPRL2;
3.50383167
cg09682796
185261

RASSF1;

TMEM115; ZMYND10

0.164
CHL1
3:239665
cg10603275
201352

0.164
MYOG; PPFIA4
1:203045044
cg00805880
17008

0.165
GNAI1
7:79764178
cg25744767
449994

0.165
LOC649133; POU2F3
11:120110887
cg17176573
314750

0.165
11-Mar
5:16179633
cg23479922
413567

0.165
PSMB9; TAP1
6:32829303
cg05062939
100976

0.165
TMEM229A
7:123673331
cg17025835
312249

0.165
CEND1; PDDC1;
11:783889
cg01741372
35661

SLC25A22

0.166
DOCK1
10:128593943
cg22665692
400049

0.166
ATP6V1A
3:113502832
cg19924544
358964

0.166
C6orf147; KHDC1
6:74024628
cg02447304
49827

0.166

22:43168851
cg24694833
433260

0.167
FAT1
4:187645118
cg01244944
26097

0.167
LILRB3
19:54728037
cg23679434
416846

0.167
SYT14
1:210111561
cg19922137
358920

0.167
ZNF844
19:12175935
cg26827373
468055

0.167
EVX2; HOXD12;
2:176957842
cg04415176
88629

HOXD13

0.167

10:131762462
cg07045241
137620

0.167
KLF8
X:56259243
cg06457357
126059

0.168
C5orf63
5:126408756
cg14340928
266559

0.168
MAGI2-AS3
7:79083408
cg22280038
394533

0.168

4:21950567
cg00688962
14541

0.169
SHISA6
17:11144043
cg13330559
245613

0.169
ARSG; SLC16A6
17:66287032
cg11879514
222640

0.169
RNF180
5:63461654
cg17370163
317926

0.169
DACH1
13:72439698
cg05510902
109333

0.169

7:55516724
cg03357999
68033

0.169
EPB41L3
18:5543801
cg00027083
665

0.170

11:67499431
cg02666610
54357

0.170
CCT8L2; TPTEP1
22:17082772
cg01660911
34237

0.171
UBTD1
10:99278449
cg10989317
207724

0.171

18:6414976
cg14352983
266773

0.171
WBSCR17
7:70597065
cg03044249
61987

0.171
MYO16
13:109352806
cg24702069
433391

0.171
ANKRD36
2:97778927
cg12623145
234729

0.171

7:152622022
cg15818671
291676

0.171
SP8
7:20824706
cg01003961
21140

0.172
CTTNBP2
7:117513101
cg05951860
117342

0.172
NAT2
8:18244861
cg12174804
227617

0.172
WBSCR17
7:70597921
cg07143083
139618

0.172
THRB
3:24536478
cg13790603
255057

0.172

16:85368973
cg02418439
49379

0.173
UBD
6:29521356
cg21632158
385088

0.173
ADAMTSL3
15:84322584
cg04138185
83155

0.173
RAB32
6:146864885
cg26252281
458030

0.174
CLEC14A
14:38724675
cg05057720
100847

0.174
DOCK1; FAM196A
10:128994603
cg03070297
62543

0.174
MDGA1
6:37618009
cg26720545
466246

0.174
BAIAP2L1
7:98029266
cg08684580
167809

0.174
LRRC4C
11:40314978
cg19849428
357643

0.174

8:7079106
cg08498719
164579

0.174
FAM43B
1:20879547
cg12768681
236962

0.174
SEMA5B
3:122694286
cg07733481
150639

0.175
SGPP2
2:223289306
cg07357987
143728

0.175

8:76320150
cg26220018
457454

0.175
CDH2
18:25757710
cg14312538
265980

0.175
CR1L
1:207842917
cg17822947
324851

0.175
NOVA1
14:27067372
cg20478129
367360

0.176
CACNA1B
9:140917431
cg13610307
251390

0.176
TRAF3
14:103367591
cg10920224
206529

0.176
IRX1
5:3596207
cg10530883
200071

0.176
BTBD3
20:11871384
cg23944804
420919

0.177

10:111216962
cg16664405
306435

0.177

10:125751413
cg20250269
363883

0.178
IRS2
13:110438578
cg02320481
47382

0.178
EVX2; HOXD13
2:176948732
cg15133351
280970

0.178
PKDCC
2:42275740
cg12630082
234855

0.179
IL5RA
3:3152916
cg21594961
384489

0.179
C5orf63
5:126408806
cg17848407
325324

0.179
GDF7
2:20870812
cg14780466
274979

0.179
HOXA10; HOXA10-
7:27206073
cg15506609
286583

HOXA9; HOXA7;

HOXA9; MIR196B

0.179
TMCC3
12:94995915
cg09162806
176158

0.179
LOC91149; RAPGEF4
2:173600676
cg00997611
21009

0.179
PHACTR1
6:12749978
cg13246235
244239

0.180
GCK; MYL7
7:44184403
cg03812172
76924

0.181

9:98981500
cg21167269
377918

0.181
GDF7
2:20870087
cg09074113
174642

0.181
KCNE1
21:35832028
cg07321776
143076

0.181
KCNK2
1:215256262
cg18794839
340940

0.181
GPR123
10:134910540
cg13750264
254277

0.182
FTSJ2; NUDT1;
7:2289097
cg12017558
224816

SNX8

0.182
KLF16
19:1852127
cg07355926
143681

0.182

2:154143768
cg18771570
340550

0.183

6:77563066
cg21291856
380079

0.184

17:54858770
cg07973125
154969

0.184
FGF12
3:192127457
cg08002883
155463

0.185
ILDR1
3:121714668
cg20356878
365522

0.185
SLC17A3
6:25882590
cg03517284
71065

0.186
FHOD3
18:34325827
cg07495405
146206

0.186
C1orf106
1:200860534
cg00909514
19113

0.186
HOXA5; HOXA6;
7:27187502
cg03529432
71326

HOXA7; LOC100133311

0.186
SH2D4B
10:82295502
cg08506606
164700

0.186
KNDC1; UTF1;
10:135044114
cg09053680
174307

VENTX

0.186
GSC2
22:19137874
cg23774356
418306

0.186
CLCA1
1:86968087
cg19807991
356943

0.187
SCTR
2:120281999
cg07176264
140350

0.187
PITX1
5:134363562
cg02037307
41774

0.187
FTSJ2; NUDT1;
7:2288716
cg13550401
250077

SNX8

0.188

8:7543899
cg12174280
227610

0.189
CLCA1
1:86968543
cg04896168
97717

0.190
NAALAD2
11:89867911
cg14304817
265815

0.190
LHX6
9:124989294
cg21469772
382370

0.190
KLF16
19:1852165
cg05006231
99848

0.191
CLCA1
1:86968255
cg26829098
468093

0.191
HLA-A
6:29910755
cg11808100
221232

0.192

19:22444593
cg03692651
74585

0.192
SERTM1
13:37248244
cg09907509
189121

0.193
CNTN4
3:2140699
cg06598836
128644

0.193

15:29862517
cg04283162
86040

0.193

4:56023751
cg10360906
197083

0.193
KIAA1217; PRINS
10:24535410
cg04122385
82818

0.194
C5orf63
5:126409211
cg10812634
204796

0.194
LOC91149; RAPGEF4
2:173600362
cg14379854
267268

0.195
ZNF471
19:57019069
cg00674365
14254

0.195
AFG3L1P; DBNDD1
16:90070038
cg16380389
301186

0.195
SH2D4B
10:82296072
cg09981929
190306

0.196
C21orf67; ITGB2;
21:46349496
cg02464073
50169

LOC100505746

0.196
NPTX2
7:98246633
cg18952796
343455

0.197
LHX6
9:124990276
cg00142257
3190

0.197
GDF7
2:20871401
cg04082016
81976

0.197
CR1L
1:207842833
cg03408135
68966

0.198
DKFZP686I15217;
6:2991147
cg06195525
121679

NQO2

0.199
PCDH7
4:30723855
cg26133769
455996

0.199
IFITM1; IFITM3
11:320956
cg14885742
276796

0.199
GNAS; GNAS-
20:57414274
cg23732978
417791

AS1

0.201
NAALAD2
11:89867819
cg05500015
109117

0.202
CPNE4
3:131246020
cg01966816
40359

0.204
EFHA2
8:16885000
cg12097222
226305

0.204
CRMP1
4:5894691
cg03544320
71665

0.205
UNC5D
8:35092876
cg06010588
118507

0.206
WTIP
19:34972145
cg10771931
204037

0.207
DNAH2; EFNB3;
17:7613764
cg22098780
391853

WRAP53

0.207
CR1L
1:207843084
cg21106486
376853

0.207
CR1; CR2
1:207669922
cg10021878
191017

0.207

13:21872349
cg14456004
268764

0.207
LOC645249
7:156814480
cg09858188
188213

0.208

13:50701619
cg01803928
36963

0.208
GALR1
18:74962133
cg03502002
70747

0.210

1:239550283
cg13985485
259057

0.210

9:96623674
cg13679303
252812

0.210
DRD5
4:9783192
cg26296488
458826

0.210
NETO1
18:70535005
cg18651870
338661

0.211
MDGA1
6:37617124
cg00807871
17056

0.212
FAM75C1
9:90531866
cg21265404
379726

0.213
TNS3
7:47621692
cg06352730
124250

0.214

2:16484904
cg23905015
420220

0.214

7:32358064
cg13207630
243593

0.216
PROZ
13:113819100
cg18105134
329535

0.216
TSHZ1; ZADH2
18:72917101
cg18449964
335368

0.217
C5orf63
5:126409310
cg15405432
284960

0.218
ZNF468
19:53361448
cg15721243
290213

0.219
FAT1
4:187644739
cg16248329
298797

0.220
CTTNBP2
7:117513835
cg16913250
310581

0.220
HES6; LOC151174;
2:239139911
cg06102419
120125

LOC643387

0.221
MAL2
8:120220882
cg06822816
133139

0.222
C5orf63
5:126409227
cg02304092
47036

0.224
LHX6
9:124988720
cg04282082
86021

0.226
HCG4; LOC554223
6:29759078
cg11036359
208507

0.229
C5orf63
5:126409061
cg18710053
339507

0.229
GPR78
4:8582249
cg01829241
37555

0.229
LHX6
9:124989337
cg13571460
250561

0.230
C5orf63
5:126409198
cg22905511
404065

0.231

2:154143677
cg07563363
147470

0.233
FCRLA
1:161675579
cg04888234
97564

0.233
FAM160B1
10:116634877
cg14964115
278020

0.235
PM20D1
1:205819251
cg14893161
276892

0.235
GDF7
2:20871279
cg07021052
137180

0.237
ANKRD27; RGS9BP
19:33165484
cg27413643
478153

0.238
MDGA1
6:37617864
cg20053110
361003

0.240

18:6414978
cg17688525
322822

0.244
ATP8B5P; RUSC2
9:35490515
cg15271616
283055

0.244
GDF7
2:20871002
cg10687131
202734

0.248

2:181987552
cg20685672
370518

0.252
ARHGAP33; C19orf55
19:36264029
cg16569309
304609

0.252
LHX6
9:124990165
cg03363289
68128

0.253
GDF7
2:20870211
cg05481257
108752

0.253
SH2D4B
10:82295723
cg24440658
429013

0.254
GDF7
2:20869434
cg27141850
473604

0.254
TSNARE1
8:143376371
cg24849373
435844

0.254
AGAP1
2:236579469
cg03451670
69806

0.255

1:41350183
cg08870646
171150

0.255
LHX6
9:124989915
cg13862711
256498

0.256
IGF1R
15:99193247
cg03437748
69502

0.256
SDK1
7:4118583
cg22535849
398182

0.257
PM20D1
1:205819492
cg24503407
430027

0.258
CLCA1
1:86968184
cg10760651
203838

0.259
WDR17
4:176987009
cg11923920
223292

0.261
ACAN
15:89354338
cg02401352
49110

0.266
TSHZ1; ZADH2
18:72917163
cg03972071
79876

0.269
MDGA1
6:37617956
cg24796644
434985

0.272
C5orf63
5:126409153
cg27097438
472827

0.275
C11orf67; RSF1
11:77532707
cg22741595
401343

0.275

6:167195910
cg06330797
123893

0.276
COL9A1
6:71022072
cg23974730
421453

0.276
INPP5A
10:134411480
cg12501287
232697

0.277
PM20D1
1:205818956
cg17178900
314798

0.277
FAM181A; FAM181A-
14:94385395
cg20022541
360557

AS1

0.279

3:120151283
cg06378561
124751

0.280
LOC255411
12:49113738
cg00007810
182

0.280
CHAF1B
21:37761363
cg22871721
403496

0.281
ASB1
2:239330383
cg13295614
245013

0.282
TNFSF8
9:117694183
cg14361804
266932

0.284
DISC1
1:231820076
cg07134368
139412

0.285
DIP2C
10:593275
cg06051619
119189

0.286
ULK4P1; ULK4P2
15:30861172
cg23804921
418678

0.287
TPO
2:1426786
cg01957222
40112

0.288
PM20D1
1:205819463
cg07167872
140186

0.290
PM20D1
1:205819179
cg14159672
262672

0.290
LOC200772
2:241896910
cg06193597
121647

0.291
PM20D1
1:205819406
cg11965913
224049

0.292
PPP2R2B
5:146253830
cg10926851
206628

0.294
LOC100133461
4:3683268
cg03965172
79742

0.297
AVL9; LSM5
7:32526065
cg26856631
468599

0.300
PM20D1
1:205819088
cg26354017
459920

0.300
MIR182; MIR183;
7:129412730
cg16069065
295914

MIR96

0.301
SCN1A
2:166930521
cg00881894
18574

0.305
RPSAP58; ZNF681
19:23941859
cg25958450
453100

0.305
CCDC130; MRI1
19:13875111
cg25755428
450171

0.317
PML
15:74345103
cg11399582
214535

0.318
C1orf109; CDCA8
1:38156652
cg06917450
135153

0.324
CELF4
18:34917603
cg20094343
361624

0.325
CLEC4F
2:71033156
cg02479782
50493

0.343
EHMT2; NEU1;
6:31838544
cg20370184
365714

SLC44A4

0.344
NCOR2
12:124827315
cg23878260
419752

0.349
PCCA
13:100989375
cg20536971
368191

0.351
ANKRD26P3;
13:19918525
cg08801017
169810

LINC00421

0.355
PPYR1
10:47083392
cg11861387
222311

0.358

5:5887642
cg26690407
465769

0.363

13:79694063
cg24941469
437468

0.366
ALLC
2:3753297
cg05971102
117729

0.378
MIR3663
10:118931160
cg17723206
323281

0.388
SERPINB9
6:2888212
cg19577958
352915

0.399
NCOR2
12:124831017
cg07474670
145798

0.404

14:22370643
cg12819537
237764

0.408
SLC37A1
21:43989949
cg08407901
162897

0.413
MRPL1
4:78852682
cg15897435
293045

0.417
C7orf26; ZNF853
7:6653510
cg08693140
167967

0.431

14:22361282
cg16702660
307151

0.432
ITIH4; MUSTN1;
3:52869263
cg24629711
432072

TMEM110; TMEM110-

MUSTN1

0.442
MAGI2-AS3
7:79083056
cg14464244
268938

0.586
PPP1R16B
20:37438823
cg18674961
338963

*UCSC hg19 Cytosine Coordinate of CpG (+strand)

The term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

The above description discloses several methods and materials of the present invention. This invention is susceptible to modifications in the methods and materials, as well as alterations in the fabrication methods and equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure or practice of the invention disclosed herein. Consequently, it is not intended that this invention be limited to the specific embodiments disclosed herein, but that it cover all modifications and alternatives coming within the true scope and spirit of the invention.

The following references are incorporated herein by reference in their entireties.

REFERENCES

1 Firestein G S. Evolving concepts of rheumatoid arthritis. Nature, 423:356-361, 2003

2 Lee differentially methylated, Kiener H P, Agarwal S K, Noss E H, Watts G F, Chisaka O, Takeichi M, Brenner M B. 2007. Cadherin-11 in synovial lining formation and pathology in arthritis. Science. 315:1006

3 Kiener H P, Niederreiter B, Lee differentially methylated, Jimenez-Boj E, Smolen J S, Brenner M B. Cadherin 11 promotes invasive behavior of fibroblast-like synoviocytes. Arthritis Rheum. 2009 May; 60(5):1305-10

4 Firestein, G S. Invasive fibroblast-like synoviocytes in rheumatoid arthritis: Passive responders or transformed aggressors? Arthritis Rheum 39:1781-1790, 1996

5 Müller-Ladner U, Kriegsmann J, Franklin B N, Matsumoto S, Geiler T, Gay R E, Gay S. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J Pathol. 1996 November; 149(5):1607-15

6 Lafyatis R, Remmers E F, Roberts A B, Yocum D E, Sporn M B, Wilder R L. 1989. Anchorage-independent growth of synoviocytes from arthritic and normal joints. Stimulation by exogenous platelet-derived growth factor and inhibition by transforming growth factor-beta and retinoids. J Clin Invest. 83:1267

7 Baier A, Meineckel I, Gay S, Pap T. Apoptosis in rheumatoid arthritis. Curr Opin Rheumatol. 2003 May; 15(3):274-9

8 Lefèvre S, Knedla A, Tennie C, Kampmann A, Wunrau C, Dinser R, Korb A, Schnäker E M, Tamer I H, Robbins P D, Evans C H, Stürz H, Steinmeyer J, Gay S, Schölmerich J, Pap T, Müller-Ladner U, Neumann E. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med. 2009 December; 15(12):1414-20

9 Pap T, Franz J K, Hummel K M, Jeisy E, Gay R, Gay S. Activation of synovial fibroblasts in rheumatoid arthritis: lack of Expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthritis Res. 2000; 2(1):59-64

10 Franz J K, Pap T, Hummel K M, Nawrath M, Aicher W K, Shigeyama Y, Müller-Ladner U, Gay R E, Gay S. Expression of sentrin, a novel antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis. Arthritis Rheum. 2000 March; 43(3):599-607

11 You X, Boyle D L, Hammaker D, Firestein G S. PUMA-mediated apoptosis in fibroblast-like synoviocytes does not require p53. Arthritis Res Ther. 2006; 8(6):R157

12 Firestein G S, F Echeverri, M Yeo, N J Zvaifler, and D R Green. Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proc Natl Acad Sci USA, 94: 10895-10900, 1997

13 Igarashi H, Hashimoto J, Tomita T, Yoshikawa H, Ishihara K. TP53 mutations coincide with the ectopic expression of activation-induced cytidine deaminase in the fibroblast-like synoviocytes derived from a fraction of patients with rheumatoid arthritis. Clin Exp Immunol. 2010 Jul. 1; 161(1):71-80

14 Inazuka M, Tahira T, Horiuchi T, Harashima S, Sawabe T, Kondo M, Miyahara H, Hayashi K. Analysis of p53 tumour suppressor gene somatic mutations in rheumatoid arthritis synovium. Rheumatology (Oxford). 2000 March; 39(3):262-6

15 Rème T, Travaglio A, Gueydon E, Adla L, Jorgensen C, Sany J. Mutations of the p53 tumour suppressor gene in erosive rheumatoid synovial tissue. Clin Exp Immunol. 1998 February; 111(2):353-8

16 Bang H, Egerer K, Gauliard A, Lüthke K, Rudolph P E, Fredenhagen G, Berg W, Feist E, Burmester G R. Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum. 2007 August; 56(8):2503-11

17 Da Sylva T R, Connor A, Mburu Y, Keystone E, Wu G E. Somatic mutations in the mitochondria of rheumatoid arthritis synoviocytes. Arthritis Res Ther. 2005; 7(4):R844-51

19 Lee S-H, D K Chang, A Goel, C R Boland, W Bugbee, D L Boyle, and G S Firestein. Microsatellite instability and suppressed DNA repair enzyme expression in rheumatoid arthritis. J Immunol, 170:2214-20, 2003

19 Christophersen N S, Helin K. Epigenetic control of embryonic stem cell fate. J Exp Med. Oct. 25, 2010; 207(11):2287-95

20 Kulis M, Esteller M. DNA methylation and cancer. Adv Genet. 2010; 70:27-56

21 Ren J, Singh B N, Huang Q, Li Z, Gao Y, Mishra P, Hwa Y L, Li J, Dowdy S C, Jiang S W. DNA hypermethylation as a chemotherapy target. Cell Signal. Feb. 21, 2011. [Epub ahead of print]

22 Turek-Plewa J, Jagodzinski P P. The role of mammalian DNA methyltransferases in the regulation of gene expression. Cell Mol Biol Lett. 2005; 10(4):631-47

23 Hollingsworth J W, Maruoka S, Boon K, Garantziotis S, Li Z, Tomfohr J, Bailey N, Potts E N, Whitehead G, Brass differentially methylated, Schwartz D A. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest. 2008 October; 118(10):3462-9

24 Miller R L. Prenatal maternal diet affects asthma risk in offspring. J Clin Invest. 2008. 118:3265-8

25 Liu C C, Fang T J, Ou T T, Wu C C, Li R N, Lin Y C, Lin C H, Tsai W C, Liu H W, Yen J H. Global DNA methylation, DNMT1, and MBD2 in patients with rheumatoid arthritis. Immunol Lett. Mar. 30, 2011; 135(1-2):96-9. Epub Oct. 16, 2010

26 Karouzakis E, Gay R E, Michel B A, Gay S, Neidhart M. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2009 December; 60(12):3613-22

27 Lee B H et al. Procainamide is a specific inhibitor of DNA methyltransferase 1. J Biol Chem. Dec. 9, 2005; 280(49):40749-56

28 Schipper R G et al. Polyamines and DNA methylation in childhood leukaemia. Biochem Soc Trans. 2007 April; 35(Pt 2):331-529 Fu L. H. et al., Methylation status of the IL-10 gene promoter in the peripheral blood mononuclear cells of rheumatoid arthritis patients. Yi Chuan. 2007 November; 29(11):1357-61.

All references cited herein, including but not limited to published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and are hereby made a part of this specification. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

Diagnosis and treatment of arthritis using epigenetics

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CPC

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