Analysis of Whole Genome Sequence and Hemostasis Phenotypes

项目总结 纤维蛋白原、凝血因子VII(FVII)和凝血因子VIII(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方面起着关键作用。同样，D-二聚体和组织 纤溶酶原激活物(TPA)反映止血系统的持续激活，纤溶酶原激活物 抑制物(PAI-1)是tPA的主要抑制物。这7个因素反映了主要的止血表型 在以人群为基础的健康成年人研究中最常被测量。全基因组关联 研究(GWAS)成功地确定了70个与这些临床相关表型相关的基因座 血栓形成和止血。全基因组测序(WGS)数据在许多研究中的可用性 为这些最初的努力做出的贡献现在将使我们能够扩大我们对基因变异的了解 有助于这些止血特征的血浆水平。拟议研究的目标是利用现有的 多种族研究中的WGS相关资源，以促进临床相关的新基因组发现 与血栓形成和止血相关的表型。 我们建立在积极协作和工作效率的悠久历史基础上，并汇集了 具有WGS数据的最大研究集合(n=37,036人)和7项止血测量 表型(纤维蛋白原、FVII、FVIII、vWF、D-二聚体、TPA和PAI-1)。WGS数据的生成已经完成 由NIH计划支持，如基因组流行病学心脏和衰老队列研究 (收费)联盟、精密医学全基因组计划(TOPMed)、共同中心 疾病基因组学(CCDG)等。该项目提供了一种协调的方法，详细说明 通过询问基因组数据，(1)利用来自10个多种族研究的WGS来评估 7种止血表型的低频率和罕见遗传变异；(2)复制了在 &gt；135,000人，来自另外26项研究，这些研究以TOPMed为参考推定了基因类型 小组；以及(3)将基因表达测量与来自大型- 对所有36项研究的止血特征进行量表常见变异的GWA，然后使用WGS进行询问 新发现的基因。这些方法将识别有助于止血特征的基因变异 然后将评估与临床结果的相关性(例如，静脉血栓栓塞症、心肌梗死 脑梗塞和中风)。 这项建议汇集了WGS广泛的资源、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 可用于在临床环境中提供精准医疗。

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.