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、凝血因子VII（FVII）和因子VIII（FVIII）及其载体蛋白血管性血友病因子 (vWF)在调节动脉和静脉血栓形成的风险中起关键作用。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，纤溶酶原激活剂 派-1是tPA的主要抑制剂。这7个因素反映了主要止血表型， 最常在健康成人的人群研究中测量。全基因组关联 研究（GWAS）成功地确定了70个基因座，这些基因座与以下相关的临床相关表型有关： 血栓形成和止血。在许多研究中，全基因组测序（WGS）数据的可用性 这将使我们能够扩大我们对遗传变异的了解， 有助于这些止血特性的血浆水平。这项研究的目的是利用现有的 多种族研究中的WGS相关资源，以促进临床相关基因组的新发现 与血栓形成和止血相关的表型。 我们建立在长期的积极合作和生产力的历史，并已汇集了 最大的研究集合，包含WGS数据（n= 37，036例受试者）和7个止血指标 表型（纤维蛋白原、FVII、FVIII、vWF、D-二聚体、tPa和派-1）。WGS数据的生成已 由NIH倡议支持，如基因组流行病学中的心脏和衰老研究队列 （CHARGE）联盟，精准医学（TOPMed）计划的Trans-Omics，共同中心 疾病基因组学（CCDG）和其他。该项目提供了一个协调的方法， 通过以下方式询问基因组数据：（1）利用来自10项多种族研究的WGS来评估 7种止血表型的低频率和罕见遗传变异;（2）在以下研究中复制显著发现： 来自另外26项研究的> 135，000名个体，基于TOPMed的插补基因型作为参考 面板;和（3）整合基因表达测量与来自大样本的汇总关联统计， 对涉及所有36项研究的止血性状的常见变体GWAS进行评分，然后使用WGS进行询问 新发现的基因这些方法将确定有助于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展，以促进证据基础， 可以用于在临床环境中提供精确的药物。