TY - JOUR
T1 - Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease
AU - INVENT Consortium
AU - Veterans Affairs’ Million Veteran Program
AU - Klarin, Derek
AU - Busenkell, Emma
AU - Judy, Renae
AU - Lynch, Julie
AU - Levin, Michael
AU - Haessler, Jeffery
AU - Aragam, Krishna
AU - Chaffin, Mark
AU - Haas, Mary
AU - Lindström, Sara
AU - Assimes, Themistocles L.
AU - Huang, Jie
AU - Min Lee, Kyung
AU - Shao, Qing
AU - Huffman, Jennifer E.
AU - Kabrhel, Christopher
AU - Huang, Yunfeng
AU - Sun, Yan V.
AU - Vujkovic, Marijana
AU - Saleheen, Danish
AU - Miller, Donald R.
AU - Reaven, Peter
AU - DuVall, Scott
AU - Boden, William E.
AU - Pyarajan, Saiju
AU - Reiner, Alex P.
AU - Trégouët, David Alexandre
AU - Henke, Peter
AU - Kooperberg, Charles
AU - Gaziano, J. Michael
AU - Concato, John
AU - Rader, Daniel J.
AU - Cho, Kelly
AU - Chang, Kyong Mi
AU - Wilson, Peter W.F.
AU - Smith, Nicholas L.
AU - O’Donnell, Christopher J.
AU - Tsao, Philip S.
AU - Kathiresan, Sekar
AU - Obi, Andrea
AU - Damrauer, Scott M.
AU - Natarajan, Pradeep
N1 - Funding Information:
Funding was received from the Department of Veterans Affairs Office of Research and Development, Million Veteran Program (grant no. MVP000). This publication does not represent the views of the Department of Veterans Affairs or the US Government. This research was also supported by three additional Department of Veterans Affairs awards (no. I01-01BX03340 to K.C. and P.W.; no I01-BX003362 to P.T. and K.M.C.; and no. I01-CX001025 to P.W.) and used the resources and facilities at the VA Informatics and Computing Infrastructure (no. VA HSR RES 13-457). S.M.D. is supported by the Veterans Administration (no. IK2-CX001780). S.K. is supported by a Research Scholar award from the Massachusetts General Hospital, the Donovan Family Foundation and the National Institutes of Health (NIH) (no. R01HL127564). P.N. is supported by the NIH/National Heart, Lung, and Blood Institute (NHLBI) (nos. K08HL140203 and R01HL142711). D.T. was financially supported by the EPIDEMIOM-VTE Senior Chair from the Initiative of Excellence of the University of Bordeaux. C.K. is supported by the NIH (grant no. HL116854). Data on coronary artery disease have been contributed by the CARDIoGRAMplusC4D investigators. Data on large artery stroke have been contributed by the MEGASTROKE investigators. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgements.html. The WHI program is funded by the NHLBI, NIH and the US Department of Health and Human Services (contract nos. HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201600004C). For a list of all the investigators who have contributed to WHI science, see https://www.whi. org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20 Long%20List.pdf. This research has been conducted using the UK Biobank resource, application no. 7089.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85074331663&partnerID=8YFLogxK
U2 - 10.1038/s41588-019-0519-3
DO - 10.1038/s41588-019-0519-3
M3 - Letter
C2 - 31676865
AN - SCOPUS:85074331663
SN - 1061-4036
VL - 51
SP - 1574
EP - 1579
JO - Nature Genetics
JF - Nature Genetics
IS - 11
ER -