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了5％的资深卫生管理（VHA） 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样本的遗传关联研究 是可以更好地理解疾病病因的潜在强大工具，因为它们可以突出显示 疾病的生物学机制，并为改善预防和 治疗。全基因组的大型关联研究（GWAS）的缺血性中风（IS）种群 在老年人中，已经确定了与该疾病相关的30多种变体。和其他一样 复杂的特征，现在挑战是确定这些变体标签和 他们改变了中风敏感性的途径。 为了补充老年人的这些努力，我们的小组采取了 研究早期发作性缺血性中风的遗传基础，这种策略一直是 成功用于许多其他复杂疾病，以识别大量效果易感性 变体并为疾病病因产生新的生物学见解。与其他复合物一样 疾病，早发中风的遗传力比老年人疾病更高，并且 专注于发病年龄或早期疾病的方法已经发现了新的中风 - 在老年疾病中不太突出的相关变体。例如，相反 在老年人中风中，动脉粥样硬化机制的重要性 在早发中风的研究中，机制可能更重要，并且可以辨别。 我们研究的科学前提是早发中风（与 以后发作的中风富含具有较高渗透率和较大效应尺寸的稀有变体，并且 这在基因的外显子（编码区）中不成比例。解决这个问题 假设，我们组装了一个年轻的中风外显子组测序联盟， 19,000例良好的早期中风病例（中风发作18 - 59年） - 包括 缺血性卒中亚型和祖先匹配的对照。我们的财团包括人口 欧洲高加索人，非洲，西班牙裔和亚洲血统。通过单独的协议 （请参阅支持信），我们目前正在这些中获得整个外显子组测序（WES） 案件及其控制。因此，此应用程序是提供行政和分析 支持WES分析。 为了识别与早发相关的变体和基因是并且是亚型，我们将 利用单个变体和负担测试方法。分析计划包括 - 我们小组通过参与使用的ART分析方法 其他测序联盟。我们的年轻中风中鉴定出的外显子变体或基因 联盟将在英国生物库中测试与中风相关的表型的关联， 与中风有关的生物标志物与最高的联盟中的中风有关，而老年人则来自英国 生物银行和顶级财团。 基因组医学是VHA中的优先事项，目的是 精确/个性化医学到VA医疗保健的最前沿。通过识别新遗传 基因座和与中风相关的新型机制，这项研究将有助于该目标。