Population genomic variation, functional biology, and the risk of venous thrombosis

摘要 精准医疗带来更健康的生活，摆脱心血管疾病的负担， 将通过建立及时，高效和有效的科学管道来加速， 遗传流行病学家和功能生物学家之间的分子遗传信息的特点。内 2个国际联盟关于止血表型和静脉 血栓栓塞症（VTE），遗传流行病学家的网络已经成功地合作，以确定和 复制了位点与VTE和血栓形成相关表型的新关联，其中一些具有 进行了功能测试。该项目的目标有两个方面：（a）协调和推进新的基因工程， 在2个止血表型国际联盟（健康和 衰老基因组流行病学研究[CHARGE]联盟）和VTE（国际静脉 血栓形成[INVENT] Consortium）;以及（B）通过进行功能生物学工作来跟踪这些发现 通过使用细胞和动物模型的实验室研究，将提供新的生物学见解。的 CHARGE止血工作组协调关键止血相关表型的基因组发现 INVENT联盟协调了来自12项研究的VTE表型的基因组发现 问题研究迄今为止的遗传学发现为调节关键基因提供了新的生物学见解。 止血蛋白和VTE风险的基因以前不知道参与生物学，如STXBP 5 与血管性血友病因子和VTE相关的TC 2N，与血管性血友病因子和VTE相关的TSPAN 15和SLC 44 A2， VTE。我们的科学生产力越来越受到限制，这是复制的挑战：随着越来越多的研究 加入联盟进行发现，可供复制的研究较少。另一种方法， 加速科学发现，是将生物信息学资源优先考虑的发现 直接在实验室进行功能测试。新发现的另一个挑战是缺乏分析 在发现工作中，在联盟设置中分析跨表型的实用工具。最近， 然而，利用遗传相关性来促进多表型研究的新方法已经 出现了，现在可以使用止血表型应用。在本申请中，我们应用这些新的 通过3个目标推进遗传和功能发现和验证工作的方法。每个目标包含 在拟议的4年项目中完成的新工作将利用现有的和即将发布的 基因组资源，以实现表征功能生理多样性的总体目标， 临床血栓形成。

Abstract The promises of precision medicine leading to healthier lives, free of the burden of cardiovascular diseases, will be hastened by creating timely, efficient, and effective scientific conduits that rapidly move newly characterized molecular genetic information between genetic epidemiologists and functional biologists. Within the setting of 2 international consortia on the genetics of hemostasis phenotypes and venous thromboembolism (VTE), a network of genetic epidemiologists have successfully collaborated to identify and to replicate novel associations of loci with VTE and thrombosis-related phenotypes, a few of which have undergone functional testing. The goals of this project are 2-fold: (a) to coordinate and advance new genetic discovery in the setting of the 2 international consortia on hemostasis phenotypes (Cohorts for Health and Aging Research in Genomic Epidemiology [CHARGE] Consortium) and VTE (International Network of Venous Thrombosis [INVENT] Consortium); and (b) to follow-up the discoveries with functional biology work conducted by laboratory-based research using cell and animal models that will provide new biologic insights. The CHARGE Hemostasis Working Group coordinates genomic discovery in key hemostasis-related phenotypes from 42 studies and the INVENT consortium coordinates genomic discovery in the VTE phenotype from 12 studies. The genetic discoveries made thus far have provided new biologic insights to the regulation of key hemostasis proteins and VTE risk in genes not previously known to be involved biologically, such as STXBP5 and TC2N, associated with von Willebrand factor and VTE, and TSPAN15 and SLC44A2, associated with VTE. A growing limitation to our scientific productivity has been the challenge of replication: as more studies join consortia for discovery, fewer studies are available for replication. An alternative approach, which accelerates scientific discovery, is to move discoveries that have been prioritized by bioinformatics resources directly to functional testing in the laboratory. Another challenge to new discovery has been the lack of analytic tools that are practical in the consortia setting to analyze across phenotypes in discovery efforts. Recently, however, new approaches that use genetic correlations to facilitate multi-phenotype investigations have emerged and can now be applied using hemostasis phenotypes. In this application, we apply these new approaches to advance genetic and functional discovery and validation efforts via 3 aims. Each aim contains novel work to be accomplished in the proposed 4-year project leverages existing and soon-to-be released genomic resources to achieve the overall goal of characterizing functional physiologic diversity that leads to clinical thrombosis in humans.