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

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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.