Whole Genome Sequence Analysis of Ischemic Stroke in the Women's Health Initiative

妇女健康倡议中缺血性中风的全基因组序列分析

• 批准号: 9290440
• 负责人: Charles L Kooperberg
• 金额: $ 59.09万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-05 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9290440
• 关键词: Adult; African American; Age; Asses; Atherosclerosis; Atrial Fibrillation; Base Sequence; Biological; Biological Markers; Biology; Blood Pressure; Brain; Cardiovascular Diseases; Cerebrum; Classification; Clinical; Code; Cognition; Cohort Studies; Collaborations; Complex; Custom; Data; Data Set; Disease; Disease Outcome; Electrocardiogram; Environment; Frequencies; Genes; Genetic; Genetic screening method; Genetic study; Genomic Segment; Genomics; Genotype; Heterogeneity; Hormones; Inflammation; International; Ischemic Stroke; Magnetic Resonance Imaging; Measures; Mediation; Methodology; Methods; Methylation; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Neurologist; Outcome; Participant; Phenotype; Plasma; Population; Precision Medicine Initiative; Proteomics; Research; Risk; Risk Factors; Sampling; Scanning; Sequence Analysis; Stroke; Testing; Thrombosis; Trans-Omics for Precision Medicine; Untranslated RNA; Variant; Veterans; White Matter Disease; Woman; Women' s Health; adjudicate; base; cardiovascular disorder risk; case control; epigenomics; exome; gene environment interaction; genetic variant; genome wide association study; genome-wide; hormone therapy; innovation; mortality; neurovascular; next generation sequencing; novel; phenotypic biomarker; power analysis; programs; prospective; protein biomarkers; rare variant; screening; sex; stroke treatment; whole genome

ABSTRACT Stroke is among the understudied disorders despite its high burden to morbidity and mortality in the US. Ischemic stroke, which is due to cerebral vessel occlusion, accounts for 80% of cases. Ischemic stroke is a complex, multi-factorial disease, with heterogeneity by age, sex, and stroke subtype. A substantial proportion of stroke risk remains unexplained. The relatively low yield of stroke genetic studies to date may reflect the heterogeneous causes and clinical presentations of the various subtypes. Many of the studies participating in stroke GWAS have included have had little or no data available on stroke-specific risk factors or other CVD outcomes, which are key to understanding causal mechanisms and potential gene–environment interactions. Next generation sequencing (NGS) and multi-omics integrative biology research offer new opportunities in the way we research and understand stroke. Whole genome sequence (WGS) data, including both coding and functional non-coding variants, are required to identify the full spectrum of contributions of uncommon variants to stroke risk. Deep WGS data are currently being generated in over 11,000 WHI participants through the NHLBI TOPMed project, including over 4,000 ischemic stroke cases. Here we propose to apply innovative statistical approaches to perform a well-powered analysis to discover, replicate, and functionally characterize new loci (particularly rare or low frequency coding and non-coding regulatory variants) for ischemic stroke (and its subtypes) using WGS and imputation. Discovery will be performed in ~4,000 incident ischemic stroke cases and over 5,000 controls from WHI with WGS through TOPMed. Single variant and gene-based tests will be performed, prioritizing ~100 genomic regions based on prior GWAS and current epigenomic and proteomic analyses. Replication will be performed through state-of-the art WGS-based exome and GWAS imputation in up to ~77,000 additional ischemic stroke cases (and controls) obtained through UKBiobank, Million Veteran Program, and the SiGN and METASTROKE stroke genomics consortia. To assess the biologic mechanism of stroke-associated genetic loci, we will further test any newly identified stroke loci for association with: (1) a rich set of CVD risk factors and ~40 plasma biomarkers related to atherosclerosis, thrombosis, inflammation, and hormones available in WHI; (2) a new, commercial panel of 184 emerging biomarkers related to neurovascular disease and CVD in 2000 WHI TOPMed samples selected on the basis of genotype. Using casual inference methodology, we will perform mediation analyses to determine mechanistic relationships between genotype, intermediate biomarker phenotype, and stroke outcome.

抽象的 中风是人们对美国发病率和死亡率的高燃烧目的地之一。 缺血性中风是由于脑血管阻塞，占病例的80％。缺血性中风是 复杂的，多因素的疾病，划分年龄，性别和中风子类型。很大的比例 中风风险仍然未知。迄今为止，中风遗传研究的相对低收率可能反映了 各种亚型的异质原因和临床表现。许多参与的研究 中风GWA包含的几乎没有或没有有关中风特异性风险因素或其他CVD的数据 结果是理解因果机制和潜在基因与环境相互作用的关键。 下一代测序（NGS）和多摩斯综合生物学研究为新的机会提供了新的机会 我们研究和理解中风的方式。整个基因组序列（WGS）数据，包括编码和 需要功能性非编码变体，以识别不常见变体的全部贡献范围 中风风险。当前，深层WGS数据正在通过11,000多名参与者生成 NHLBI最佳项目，包括4,000多个缺血性中风病例。在这里，我们建议应用创新 统计方法执行功能良好的分析以发现，复制并在功能上表征 缺血性中风的新局部（部分或低频编码和非编码调节变体）（和 它的亚型）使用WGS和插补。发现将在〜4,000个事件中进行缺血案例进行 从WGS到Topmed，WHI的5,000多个控件。单个变体和基于基因的测试将是 根据先前的GWA和当前的表观基因组和蛋白质组学进行了优先级的〜100个基因组区域 分析。复制将通过最先进的基于WGS的外来组和GWAS归为 通过UKBiobank获得的数百万退伍军人获得的最多约77,000个其他缺血性中风病例（和对照） 程序，以及标志和元震动中风基因组学联盟。评估生物学机制 中风相关的遗传基因座，我们将进一步测试任何新鉴定的中风基因座以与：（1）丰富 CVD危险因素和约40个与动脉粥样硬化，血栓形成，炎症和 在Whi中有骑马； （2）与神经血管相关的184个新兴生物标志物的新商业面板 2000年的疾病和CVD是根据基因型选择的最高样品。使用休闲推理 方法论，我们将进行调解分析，以确定基因型之间的机械关系 中间生物标志物表型和中风结果。