Analysis of Whole Genome Sequence and Hemostasis Phenotypes

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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.