Analysis of Whole Genome Sequence and Hemostasis Phenotypes

全基因组序列和止血表型分析

• 批准号: 9886277
• 负责人: Alanna C Morrison
• 金额: $ 71.14万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-05 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886277
• 关键词: Adult; Affect; Aging; Alteplase; Blood Coagulation Factor VII; Cardiovascular system; Carrier Proteins; Clinical; Collaborations; Collection; Computer Analysis; Data; Disease; European; Event; Exons; F8 gene; Factor VIII; Fibrin; Fibrin fragment D; Fibrinogen; Frequencies; Gene Expression; Generations; Genetic; Genetic Enhancer Element; Genetic Variation; Genome; Genomics; Genotype; Goals; Heart; Hemostatic Agents; Hemostatic function; Individual; Knowledge; Measurement; Measures; Myocardial Infarction; Outcome; Phenotype; Plasma; Plasminogen Inactivators; Play; Population Study; Predictive Factor; Predisposition; Productivity; Recording of previous events; Research; Research Personnel; Resources; Risk; Slide; Stroke; System; Technology; Testing; Thrombosis; Trans-Omics for Precision Medicine; United States National Institutes of Health; Variant; Venous Thrombosis; base; clinically relevant; cohort; evidence base; functional genomics; gene discovery; genome sequencing; genome wide association study; genome-wide; genomic data; genomic epidemiology; inhibitor/antagonist; precision medicine; programs; statistics; trait; transcriptome; venous thromboembolism; von Willebrand Factor; whole genome; working group

PROJECT SUMMARY Fibrinogen, coagulation factor VII (FVII) and factor VIII (FVIII), and its carrier protein von Willebrand factor (vWF) play key roles in modulating the risk of arterial and venous thrombosis. Similarly, D-dimer and tissue plasminogen activator (tPA) reflect ongoing activation of the hemostatic system, and plasminogen activator inhibitor (PAI-1) is the principal inhibitor of tPA. These 7 factors reflect the primary hemostasis phenotypes that have been most commonly measured in population-based studies of healthy adults. Genome-wide association studies (GWAS) successfully identified 70 loci contributing to these clinically relevant phenotypes related to thrombosis and hemostasis. The availability of whole genome sequencing (WGS) data in many of the studies that contributed to these initial efforts will now allow us to expand our knowledge of the genetic variation contributing to plasma levels of these hemostasis traits. The goal of the proposed research is to utilize existing WGS-related resources in multi-ethnic studies to facilitate new genomic discovery in clinically-relevant phenotypes related to thrombosis and hemostasis. We build upon a long-standing history of active collaboration and productivity, and have assembled the largest collection of studies with WGS data (n=37,036 individuals) and measurements for the 7 hemostasis phenotypes (fibrinogen, FVII, FVIII, vWF, D-dimer, tPa, and PAI-1). Generation of WGS data has been supported by NIH initiatives such as the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Trans-Omics for Precision Medicine (TOPMed) Program, the Centers for Common Disease Genomics (CCDG), and others. This project provides a coordinated approach for detailed interrogation of genomic data by, (1) utilizing WGS from 10 multi-ethnic studies to assess the contribution of low frequency and rare genetic variation to 7 hemostasis phenotypes; (2) replicating significant findings in >135,000 individuals from an additional 26 studies with imputed genotypes based on TOPMed as a reference panel; and (3) integrating gene expression measurements with summary association statistics from a large- scale common variant GWAS for hemostasis traits involving all 36 studies, then using WGS to interrogate newly discovered genes. These approaches will identify genetic variation contributing to hemostasis traits that will then be evaluated for association with clinical outcomes (e.g., venous thromboembolism, myocardial infarction, and stroke). This proposal brings together extensive WGS resources, hemostasis phenotypes, and capitalizes on advances in genomic technologies and computational analysis in order to contribute to the evidence base that may be used to deliver precision medicine in clinical settings.

项目摘要 纤维蛋白原，凝结因子VII（FVII）和VIII因子（FVIII）及其载体蛋白von Willebrand因子 （vwf）在调节动脉和静脉血栓形成的风险中发挥关键作用。同样，D-二聚体和组织 纤溶酶原激活剂（TPA）反映了止血系统的持续激活和纤溶酶原激活剂 抑制剂（PAI-1）是TPA的主要抑制剂。这7个因素反映了主要的止血表型 在健康成年人的基于人群的研究中最常衡量。全基因组关联 研究（GWAS）成功地鉴定了70个基因座，这些基因座有助于这些临床相关的表型 血栓形成和止血。在许多研究中，整个基因组测序（WGS）数据的可用性 促进这些初步努力的原因将使我们能够扩大对遗传变异的了解 导致这些止血性状的血浆水平。拟议的研究的目的是利用现有 多民族研究中与WGS相关的资源，以促进与临床相关的新基因组发现 与血栓形成和止血有关的表型。 我们以积极的协作和生产力的长期历史为基础，并汇集了 WGS数据（n = 37,036个个体）的最大研究收集和7个止血的测量值 表型（纤维蛋白原，FVII，FVIII，VWF，D-Dimer，TPA和PAI-1）。 WGS数据的生成已经 在NIH倡议的支持下，例如基因组流行病学的心脏和衰老研究 （收费）财团，精密医学的跨词（TopMed）计划，共同的中心 疾病基因组学（CCDG）等。该项目为详细的方法提供了协调的方法 通过（1）利用10个多种族研究的WG对基因组数据进行询问 低频和罕见的遗传变异到7种止血表型； （2）复制重大发现 > 135,000名基于最高基因型的26项研究中的135,000个人作为参考 控制板; （3）将基因表达测量与汇总关联统计数据整合到大的 缩放涉及所有36项研究的止血性状的常见变体GWA，然后使用WG进行询问 新发现的基因。这些方法将确定造成止血性状的遗传变异 然后将评估与临床结果的关联（例如，静脉血栓栓塞，心肌 梗塞和中风）。 该提案汇集了广泛的WGS资源，止血表型，并利用 基因组技术和计算分析的进步，以促进证据基础 可用于在临床环境中提供精确药物。