Whole Exome Sequencing Study of Early-Onset Ischemic Stroke

中风和相关疾病占退伍军人健康管理局(VHA)的5% 病人护理资源，每年约有15,000名退伍军人接受急性住院护理 卒中。基于大量仔细表型研究对象的遗传关联研究 是更好地理解疾病病因的潜在强大工具，因为它们可以强调 疾病的生物机制，并指出了改进预防和 治疗。缺血性卒中(IS)人群的大型全基因组关联研究(GWAS) 在老年人中，已经发现了30多个与这种疾病有关的变异。与其他产品一样 复杂的特征，现在的挑战是确定这些变异标记的基因和 它们改变中风易感性的途径。 为了在老年人中补充这些努力，我们小组采取了以下战略 研究早发性缺血性中风的遗传基础，这是一种已经被 成功地用于许多其他复杂疾病以确定大效应易感性 并产生对疾病病因学的新的生物学见解。与其他复合体一样 与老年疾病相比，早发性中风的遗传率更高 关注发病年龄或早发性疾病的方法发现了新的中风- 在较早发病的疾病中不太明显的相关变异。例如，相比之下， 由于动脉粥样硬化机制在老年卒中的重要性，血栓前病变 在早发性中风的研究中，机制可能更重要和更容易辨别。 我们研究的科学前提是早发性中风(与此形成对比 晚发性卒中)丰富了具有高外显率和大效应大小的稀有变异 不成比例地出现在基因的外显子(编码区)中。要解决这个问题 假设，我们已经组建了一个年轻的卒中外显子组测序联盟 19,000例表型良好的早发性中风病例(发病18-59岁)--包括 缺血性卒中亚型和祖先匹配的对照组。我们的财团包括人口 有欧洲高加索人、非洲人、西班牙人和亚洲人血统。通过单独的协议 (见支持函)，我们目前正在获得这些基因的完整外显子组测序(WES) 病例及其对照。因此，此应用程序是为了提供管理和分析 支持WES分析。 为了确定与早发性IS和IS亚型相关的变异和基因，我们将 同时使用单变量和负荷测试方法。分析计划包括 我们团队通过参与以下活动而使用的最先进的分析方法 其他测序联盟。在我们年轻的中风中发现的外显子变异或基因 该联盟将在英国生物库中接受与中风相关表型的关联测试， TOPMed联盟中与中风相关的生物标记物，以及年龄较大的患者来自英国 Biobank和TOPMed财团。 基因组医学是VHA的优先事项，目标是使 精准/个性化医疗走在退伍军人管理局医疗保健的前沿。通过识别新的基因 与中风相关的基因座和新机制，这项研究将有助于实现这一目标。

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.