Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease

• Type of Material: Article
• Authors: Derek Klarin, VA Boston Healthcare System; Emma Busenkell, Harvard University; Renae Judy, Corporal Michael Crescenz Vet Affairs Med Ctr; Julie Lynch, University of Massachusetts; Michael Levin, University of Pennsylvania; Jeffery Haessler, Fred Hutchinson Cancer Research Center; Krishna Aragam, Harvard University; Yan Sun, Emory University; Peter Wilson, Emory University; Pradeep Natarajan, Vet Affairs Boston Healthcare Syst
• Language: English
• Date: 2019-11-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © The Author(s), under exclusive licence to Springer Nature America, Inc. 2019
• Final Published Version (URL): http://dx.doi.org/10.1038/s41588-019-0519-3
• Title of Journal or Parent Work: Nature Genetics
• Volume: 51
• Issue: 11
• Start Page: 1574
• End Page: +
• Grant/Funding Information: P Natarajan is supported by the NIH/NHLBI [K08HL140203 and R01HL142711].; D Trégouët was financially supported by the “EPIDEMIOM-VTE” Senior Chair from the Initiative of Excellence of the University of Bordeaux.; S Kathiresan is supported by a Research Scholar award from the Massachusetts General Hospital (MGH), the Donovan Family Foundation, and the National Institutes of Health [R01HL127564].; S Damrauer is supported by the Veterans Administration [IK2-CX001780].; C Kabrhel is supported by the NIH [HL116854].; This research was also supported by three additional Department of Veterans Affairs awards (I01-01BX03340 [K Cho/P Wilson], I01-BX003362 [P Tsao/KM Chang], and I01-CX001025 [P Wilson]) and used resources and facilities at the VA Informatics and Computing Infrastructure (VINCI), VA HSR RES 13-457.; J Concato is now with the U.S. Food and Drug Administration.; Funding from the Department of Veterans Affairs Office of Research and Development, Million Veteran Program Grant #MVP000.
• Keywords: Science & Technology; Biobank; Epidemiology; Rosuvastatin; Fibrosis; Resolution; Individuals; Plasminogen-activator inhibitor 1; Metaanalysis; Thrombosis; GWAS; Life Sciences & Biomedicine; Genetics & Heredity
• Research Categories: Engineering, Biomedical; Biology, Genetics; Health Sciences, Medicine and Surgery; Health Sciences, Epidemiology

Abstract

Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.