Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors

Author:

Thibord Florian12ORCID,Klarin Derek34ORCID,Brody Jennifer A.5,Chen Ming-Huei12ORCID,Levin Michael G.6ORCID,Chasman Daniel I.78ORCID,Goode Ellen L.9,Hveem Kristian10,Teder-Laving Maris11,Martinez-Perez Angel12ORCID,Aïssi Dylan1314ORCID,Daian-Bacq Delphine1516,Ito Kaoru17ORCID,Natarajan Pradeep181920ORCID,Lutsey Pamela L.21ORCID,Nadkarni Girish N.222324ORCID,de Vries Paul S.25ORCID,Cuellar-Partida Gabriel26,Wolford Brooke N.27ORCID,Pattee Jack W.2829,Kooperberg Charles30ORCID,Braekkan Sigrid K.3132ORCID,Li-Gao RuifangORCID,Saut Noemie33ORCID,Sept Corriene34,Germain Marine131416ORCID,Judy Renae L.3536,Wiggins Kerri L.5ORCID,Ko Darae237ORCID,O’Donnell Christopher J.1838ORCID,Taylor Kent D.39ORCID,Giulianini Franco7,De Andrade Mariza9ORCID,Nøst Therese H.10ORCID,Boland Anne1516ORCID,Empana Jean-Philippe4041ORCID,Koyama Satoshi171920,Gilliland Thomas181920ORCID,Do Ron222342ORCID,Huffman Jennifer E.43,Wang Xin26ORCID,Zhou Wei44,Manuel Soria Jose12ORCID,Carlos Souto Juan1245ORCID,Pankratz Nathan46ORCID,Haessler Jeffery30,Hindberg Kristian31,Rosendaal Frits R.36ORCID,Turman Constance34ORCID,Olaso Robert1516ORCID,Kember Rachel L.47,Bartz Traci M.48ORCID,Lynch Julie A.49ORCID,Heckbert Susan R.50ORCID,Armasu Sebastian M.9,Brumpton Ben10ORCID,Smadja David M.5152ORCID,Jouven Xavier5354,Komuro Issei55ORCID,Clapham Katharine R.561820ORCID,Loos Ruth J.F.22ORCID,Willer Cristen J.27ORCID,Sabater-Lleal Maria1257ORCID,Pankow James S.21ORCID,Reiner Alexander P.3050ORCID,Morelli Vania M.3132,Ridker Paul M78ORCID,Vlieg Astrid van Hylckama36,Deleuze Jean-François151658,Kraft Peter34,Rader Daniel J.659ORCID,Min Lee Kyung60ORCID,Psaty Bruce M.56150ORCID,Heidi Skogholt Anne10,Emmerich Joseph6263,Suchon Pierre3364,Rich Stephen S.65ORCID,Vy Ha My T.2223ORCID,Tang Weihong21ORCID,Jackson Rebecca D.66,Hansen John-Bjarne3132,Morange Pierre-Emmanuel3364,Kabrhel Christopher6768,Trégouët David-Alexandre131416,Damrauer Scott M.355969ORCID,Johnson Andrew D.12ORCID,Smith Nicholas L.507071ORCID,

Affiliation:

1. Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Framingham, MA (F.T., M.-H.C., A.D.J.).

2. Framingham Heart Study, Boston University, Framingham, MA (F.T., M.-H.C., D. Ko, A.D.J.).

3. Division of Vascular Surgery, Stanford University School of Medicine, CA (D. Klarin).

4. Veterans Affairs Palo Alto Healthcare System, CA (D. Klarin).

5. Cardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., B.M.P.), University of Washington, Seattle.

6. Departments of Medicine (M.G.L., D.J.R), Perelman School of Medicine, University of Pennsylvania, Philadelphia.

7. Division of Preventive Medicine (D.I.C., F.G., P.M.R.), Brigham and Women’s Hospital, Boston, MA.

8. Harvard Medical School (D.I.C., P.M.R.), Boston, MA.

9. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN (E.L.G., M.D.A., S.M.A.).

10. K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim (K. Hveem, T.H.N., B.B., A.H.S.).

11. Institute of Genomics, University of Tartu, Estonia (M.T.-L.).

12. Genomics of Complex Disease Unit, Institut d’Investigació Biomèdica Sant Pau, Barcelona, Spain (A.M.-P., J.M.S., J.C.S., M.S.-L.).

13. Bordeaux Population Health Research Center, University of Bordeaux, France (D.A., M.G., D.-A.T.).

14. UMR1219, Institut national de la santé et de la recherche médicale, Bordeaux, France (D.A., M.G., D.-A.T.).

15. Centre National de Recherche en Génomique Humaine, CEA, Université Paris-Saclay, Evry, France (D.D.-B., A.B., R.O., J.-F.D.).

16. Laboratory of Excellence on Medical Genomics, GenMed, Paris, France (D.D.-B., M.G., A.B., R.O., J.-F.D., D.-A.T.).

17. Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (K.I., S.K.).

18. Department of Medicine (P.N., T.G., K.R.C., C.J.O.), Boston, MA.

19. Cardiovascular Research Center (P.N., S.K., T.G.), Massachusetts General Hospital, Boston.

20. Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K., T.G., K.R.C.).

21. Division of Epidemiology and Community Health, School of Public Health (P.L.L., J.S.P., W.T.), University of Minnesota, Minneapolis.

22. Charles Bronfman Institute for Personalized Medicine (G.N.K., R.D., R.J.F.L., H.M.T.V.), Icahn School of Medicine at Mount Sinai, New York, NY.

23. Department of Genetics and Genomic Sciences (G.N.K., R.D., H.M.T.V.), Icahn School of Medicine at Mount Sinai, New York, NY.

24. Division of Nephrology, Department of Medicine (G.N.K.), Icahn School of Medicine at Mount Sinai, New York, NY.

25. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston (P.S.d.V.).

26. 23andMe, Inc, Sunnyvale, CA (G.C.-P., X.W.).

27. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor (B.N.W., C.J.W.).

28. Division of Biostatistics (J.W.P.), University of Minnesota, Minneapolis.

29. Center for Innovative Design & Analysis and Department of Biostatistics & Informatics, Colorado School of Public Health, Aurora (J.W.P.).

30. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (C. Kooperberg, J.H., A.P.R.).

31. Thrombosis Research Center, UiT—Arctic University of Norway, Tromsø (S.K.B., K. Hindberg, V.M.M., J.-B.H.).

32. Division of Internal Medicine, University Hospital of North Norway, Tromsø (S.K.B., V.M.M., J.-B.H.).

33. Hematology Laboratory, La Timone University Hospital of Marseille, France (N.S., P.S., P.-E.M.).

34. Department of Epidemiology, Harvard T.H. Chan Harvard School of Public Health, Boston, MA (C.S., C.T., P.K.).

35. Surgery (R.L.J., S.M.D), Perelman School of Medicine, University of Pennsylvania, Philadelphia.

36. Clinical Epidemiology, Leiden University Medical Center, Netherlands (R.L.-G., F.R.R., A.v.H.V.).

37. Section of Cardiovascular Medicine, Boston University School of Medicine, MA (D.K.).

38. Cardiology Section, Department of Medicine (C.J.O.), Veterans Affairs Boston Healthcare System, MA.

39. Institute for Translational Genomics and Population Sciences, Lundquist Institute for Biomedical Innovation, Torrance, CA (K.D.T.).

40. Integrative Epidemiology of Cardiovascular Diseases, Université Paris Cité, Paris Cardiovascular Research Center, France (J.-P.E.).

41. Department of Cardiology, Assistance Publique – Hôpitaux de Paris, Hopital Européen Georges Pompidou, Paris, France (J.-P.E.).

42. BioMe Phenomics Center (R.D.), Icahn School of Medicine at Mount Sinai, New York, NY.

43. MAVERIC (J.E.H.), Veterans Affairs Boston Healthcare System, MA.

44. Analytic and Translational Genetics Unit, Department of Medicine (W.Z.), Massachusetts General Hospital, Boston.

45. Unit of Thrombosis and Hemostasis, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (J.C.S.).

46. Department of Laboratory Medicine and Pathology (N.P.), University of Minnesota, Minneapolis.

47. Psychiatry (R.L.K.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.

48. Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine (T.M.B.), University of Washington, Seattle.

49. Epidemiology, University of Utah, Salt Lake City (J.A.L.).

50. Department of Epidemiology (S.R.H., A.P.R., B.M.P., N.L.S.), University of Washington, Seattle.

51. Hematology Department and Biosurgical Research Laboratory (Carpentier Foundation), European Georges Pompidou Hospital, Assistance Publique Hôpitaux de Paris, France (D.M.S.).

52. Innovative Therapies in Haemostasis, Institut national de la santé et de la recherche médicale (D.M.S.), Université de Paris, France.

53. Integrative Epidemiology of Cardiovascular Diseases (X.J.), Université Paris Descartes, Sorbonne Paris Cité, France.

54. Paris Cardiovascular Research Center, Inserm U970, Institut national de la santé et de la recherche médicale (X.J.), Université Paris Descartes, Sorbonne Paris Cité, France.

55. Department of Cardiovascular Medicine, University of Tokyo, Japan (I.K.).

56. Division of Pulmonary and Critical Care Medicine (K.R.C.), Brigham and Women’s Hospital, Boston, MA.

57. Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden (M.S.-L.).

58. Centre D’Etude du Polymorphisme Humain, Fondation Jean Dausset, Paris, France (J.-F.D.).

59. Genetics (D.J.R, S.M.D.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.

60. HUNT Research Center, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger (K. Hveem).

61. Department of Health Systems and Population Heath (B.M.P.), University of Washington, Seattle.

62. Department of Vascular Medicine, Paris Saint-Joseph Hospital Group (J.E.), Université de Paris, France.

63. UMR1153, Institut national de la santé et de la recherche médicale CRESS, Paris, France (J.E.).

64. C2VN, Institut national de la santé et de la recherche médicale, institut national de recherche pour l’agriculture, l’alimentation et l’environnement, Aix-Marseille University, France (P.S., P.-E.M.).

65. Center for Public Health Genomics, University of Virginia, Charlottesville (S.S.R.).

66. College of Medicine, Ohio State University, Columbus (R.D.J.).

67. Emergency Medicine (C. Kabrhel), Boston, MA.

68. Emergency Medicine (C. Kabrhel), Massachusetts General Hospital, Boston.

69. Corporal Michael J. Crescenz Philadelphia Veterans Affairs Medical Center, PA (S.M.D.).

70. Kaiser Permanente Washington Health Research Institute, Seattle (N.L.S.).

71. Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA (N.L.S.).

Abstract

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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