Whole Exome Sequencing Study of Early-Onset Ischemic Stroke

早发性缺血性中风的全外显子组测序研究

• 批准号: 10514591
• 负责人: JOHN W. COLE
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514591
• 关键词: Acute; Address; Adult; African; African ancestry; Age; Age of Onset; Agreement; Asian ancestry; Big Data; Biological; Biological Markers; Caucasians; Cause of Death; Cessation of life; Code; Collaborations; Complement; Complex; Consumption; Data; Development; Disease; Drug Targeting; Economic Burden; Elderly; Etiology; European; Exons; Genes; Genetic; Genetic Code; Genetic Risk; Genetic study; Genome; Genomic medicine; Genotype; Goals; Healthcare; Heritability; Hispanic; Hispanic ancestry; Individual; International; Investments; Ischemic Stroke; Leadership; Letters; Methods; Onset of illness; Pathway interactions; Patient Care; Penetrance; Phenotype; Population; Positioning Attribute; Predisposition; Prevention; Prevention strategy; Proteins; Research; Resources; Role; Sampling; Stress; Stroke; Stroke prevention; Susceptibility Gene; Testing; Trans-Omics for Precision Medicine; Variant; Veterans; Veterans Health Administration; biobank; disability burden; early onset; exome sequencing; experience; genetic association; genetic variant; genome wide association study; genomic locus; improved; industry partner; inpatient service; insight; non-genetic; novel; novel therapeutic intervention; personalized medicine; programs; rare variant; tool; trait; treatment strategy

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.

中风和相关疾病消耗退伍军人健康管理局 (VHA) 5% 的资金 患者护理资源，每年约有 15,000 名退伍军人接受急性住院护理 中风。基于仔细表型受试者的大样本的遗传关联研究 是更好地了解疾病病因的潜在强大工具，因为它们可以强调 疾病的生物学机制，并为改善预防和治疗指明了道路 治疗。缺血性中风 (IS) 人群的大型全基因组关联研究 (GWAS) 在老年人中已发现超过 30 种与这种疾病相关的变异。与其他 复杂的性状，现在的挑战是识别这些变体标记的基因以及 它们改变中风易感性的途径。 为了补充老年人的这些努力，我们的团队采取了以下战略： 研究早发性缺血性中风的遗传基础，这一策略已被 成功用于许多其他复杂疾病以确定大效应易感性 变体并对疾病病因产生新的生物学见解。与其他复杂的 疾病，早发性中风比老年发病的疾病具有更高的遗传力，并且 关注发病年龄或早发疾病的方法发现了新的中风- 相关变异在老年发病的疾病中不太明显。例如，相比之下 动脉粥样硬化机制在老年中风中的重要性 在早发性卒中的研究中，机制可能更重要、更容易辨别。 我们研究的科学前提是早发性中风（与 晚发性中风）丰富了具有高外显率和大效应量的罕见变异， 不成比例地出现在基因的外显子（编码区）中。为了解决这个问题 假设，我们已经组建了一个年轻中风外显子组测序联盟，成员超过 19,000 例表型良好的早发性中风病例（中风发病年龄 18-59 岁） - 包括 缺血性中风亚型和血统匹配对照。我们的财团包括人口 欧洲高加索人、非洲人、西班牙人和亚洲人的血统。通过单独的协议 （参见支持信），我们目前正在这些领域获得全外显子组测序（WES） 案例及其控制。因此，该应用程序旨在提供管理和分析 支持WES分析。 为了识别与早发 IS 和 IS 亚型相关的变异和基因，我们将 利用单变体和负荷测试方法。分析计划包括现状 我们的团队通过参与经验丰富地使用了最先进的分析方法 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 联盟将在英国生物库中测试与中风相关表型的关联， TOPMed 联盟中与中风相关的生物标志物以及来自英国的老年发病 IS 生物银行和 TOPMed 联盟。 基因组医学是 VHA 的优先事项，其目标是 精准/个性化医疗走在退伍军人管理局医疗保健的最前沿。通过识别新的基因 与中风相关的位点和新机制，这项研究将有助于实现这一目标。