Whole Exome Sequencing Study of Early-Onset Ischemic Stroke

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Stroke and related diseases consume 5% of Veteran Health Administration (VHA) patient care resources, and about 15,000 Veterans annually receive acute inpatient care for stroke. Genetic association studies based on large samples of carefully phenotyped subjects are potentially powerful tools for better understanding disease etiology as they can highlight biological mechanisms underlying disease and point the way to improved prevention and treatment. Large genome-wide association studies (GWAS) of ischemic stroke (IS) populations in older adults have identified over 30 variants associated with this disorder. As with other complex traits, the challenge now is to identify the genes that these variants tag and the pathways through which they alter stroke susceptibility. To complement these efforts in older adults our group has pursued the strategy of studying the genetic underpinnings of early-onset ischemic stroke, a strategy that has been used successfully for many other complex diseases to identify large effect susceptibility variants and to generate novel biologic insights into disease etiology. As with other complex disorders, early-onset stroke has a higher heritability than older-onset disease, and approaches focusing on age of onset or early-onset disease have uncovered new stroke- associated variants that were less prominent in older-onset disease. For example, in contrast to the importance of atherosclerotic mechanisms in older-onset stroke, prothrombotic mechanisms are likely to be more important and discernable in studies of early-onset stroke. The scientific premise underlying our study is that early-onset stroke (in contrast to later-onset stroke) is enriched for rare variants with high penetrance and large effect sizes and that occur disproportionately in the exons (coding regions) of genes. To address this hypothesis, we have assembled a Young Stroke Exome Sequencing Consortium with over 19,000 well-phenotyped early-onset stroke cases (stroke onset 18-59 years) - including ischemic stroke subtype, and ancestry-matched controls. Our consortium includes populations of European Caucasian, African, Hispanic and Asian ancestry. Through a separate agreement (see letter of support), we are currently obtaining whole exome sequencing (WES) in these cases and their controls. Thus, this application is to provide administrative and analysis support for the WES analysis. To identify variants and genes associated with early-onset IS and IS subtypes, we will utilize both single variant and burden testing approaches. The analysis plan includes state-of- the-art analysis methods that our group is experienced in using through our participation in other sequencing consortia. Exonic variants or genes identified in our young stroke consortium will be tested for association with stroke-related phenotypes in the UK Biobank, biomarkers related to stroke in the TOPMed Consortium, and older-onset IS from the UK Biobank and TOPMed Consortium. Genomic medicine is a priority within the VHA with the goal of bringing precision/personalized medicine to the forefront of VA health care. By identifying new genetic loci and novel mechanisms associated with stroke, this study will contribute towards that goal.