Research Project
10250540
Project Summary/Abstract Stroke is the third leading cause of death and the leading cause of adult disability in the United States. More adults are affected by stroke each year than Alzheimer?s disease, multiple sclerosis, amyotrophic lateral sclerosis or Parkinson?s disease. Intracerebral hemorrhage (ICH) represents the most severe subtype of stroke. An estimated 40-50% of ICH victims will die and more than 80% of survivors remain disabled. Patients with ICH share histopathological features with other forms of cerebral small vessel disease (CSVD) caused by hypertension and cerebral amyloid angiopathy. CSVD is a key component of progressive neurologic decline in Alzheimer?s disease and vascular dementia, and nearly half of ICH survivors develop dementia within 4 years. Our investigators have previously collaborated to publish the largest genome wide association study of ICH with ~1500 cases, which identified novel genetic factors that have since gone on to be replicated in CSVD phenotypes including white matter hyperintensity and small vessel stroke. With greater sample size, we will uncover additional risk factors for ICH and through those mechanisms, Alzheimer?s and vascular dementias. The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study originally recruited over 3000 cases of spontaneous hemorrhage with equal power among white, black and Hispanic cases. The study design begins with the philosophy that both ethnicity-specific and non-specific risk factors for ICH may exist, and numerous ERICH publications support this. We propose to combine additional ICH cases from around the world to maximize the power of our study to identify novel genetic variants across ethnicities. We have identified over 21,000 cases that have either completed genotyping or have samples available to assess genetic risk of ICH. However, the critical first step is to perform careful phenotype harmonization, specifically in location of hemorrhage which stratifies patients clinically, histopathologically, and genetically. Different studies have used different location definitions which if not harmonized will limit study power due to case misclassification. We have previously performed phenotype harmonization across our two centers for both ICH case status and location in >5,000 cases across 3 NIH-funded studies. We intend to complete harmonization on cases with available data, and expand harmonization to related imaging CSVD phenotypes and clinical outcomes. Next, we will combine genomic data to create polygenic risk scores (PRS) to stratify cumulative genetic risk of ICH at the individual level, which may provide a near-term opportunity to leverage genomic association data to improve clinical care. Finally, we will maximally share all association results and phentoypes through the Cerebrovascular Disease Knowledge Portal, a freely-accessible on-line collaborative resource established with NINDS support. If successful, we will have identified risk factors for ICH, subtypes by location and across CSVD neuroimaging features, which will be valuable as targets for rational therapeutic development. We will also have built PRS for ICH risk and outcome, as a tool to stratify individuals by ICH risk and provide prognostic information on outcomes.
