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Nat Genet. 2019 Nov;51(11):1574-1579. doi: 10.1038/s41588-019-0519-3. Epub 2019 Nov 1.

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

Author information

1
Veterans Affairs Boston Healthcare System, Boston, MA, USA.
2
Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
3
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4
Division of Vascular Surgery and Endovascular Therapy, University of Florida School of Medicine, Gainesville, FL, USA.
5
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
6
Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.
7
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
8
Veterans Affairs Informatics and Computing Infrastructure, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, UT, USA.
9
University of Massachusetts College of Nursing & Health Sciences, Boston, MA, USA.
10
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
11
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
12
Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
13
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
14
Massachusetts Veterans Epidemiology Research and Information Center, Veterans Affairs Boston Healthcare System, Boston, MA, USA.
15
Center for Healthcare Organization and Implementation Research, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, USA.
16
Boston University School of Public Health, Department of Health Law, Policy & Management, Boston, MA, USA.
17
Center for Vascular Emergencies, Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA.
18
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
19
Department of Epidemiology, Emory University Rollins School of Public Health, Department of Biomedical Informatics Emory University School of Medicine, Atlanta, GA, USA.
20
Atlanta Veterans Affairs Health Care System, Decatur, GA, USA.
21
Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, Philadelphia, PA, USA.
22
Phoenix Veterans Affairs Health Care System, Phoenix, AZ, USA.
23
Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
24
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
25
Bordeaux Population Health Research Center (INSERM UMR S 1219), University of Bordeaux, Bordeaux, France.
26
Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
27
Clinical Epidemiology Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.
28
Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.
29
Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA.
30
Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA.
31
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
32
Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
33
Verve Therapeutics, Cambridge, MA, USA.
34
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
35
Veterans Affairs Boston Healthcare System, Boston, MA, USA. pnatarajan@mgh.harvard.edu.
36
Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. pnatarajan@mgh.harvard.edu.
37
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. pnatarajan@mgh.harvard.edu.
38
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. pnatarajan@mgh.harvard.edu.

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.

PMID:
31676865
PMCID:
PMC6858581
[Available on 2020-05-01]
DOI:
10.1038/s41588-019-0519-3

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