. 2022 Oct 18;146(16):1225-1242.

doi: 10.1161/CIRCULATIONAHA.122.059675. Epub 2022 Sep 26.

Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors

Florian Thibord^#^{1

2}, Derek Klarin^#^{3

4}, Jennifer A Brody⁵, Ming-Huei Chen^{1

2}, Michael G Levin⁶, Daniel I Chasman^{7

8}, Ellen L Goode⁹, Kristian Hveem¹⁰, Maris Teder-Laving¹¹, Angel Martinez-Perez¹², Dylan Aïssi^{13

14}, Delphine Daian-Bacq^{15

16}, Kaoru Ito¹⁷, Pradeep Natarajan^{18

19

20}, Pamela L Lutsey²¹, Girish N Nadkarni^{22

23

24}, Paul S de Vries²⁵, Gabriel Cuellar-Partida²⁶, Brooke N Wolford²⁷, Jack W Pattee^{28

29}, Charles Kooperberg³⁰, Sigrid K Braekkan^{31

32}, Ruifang Li-Gao, Noemie Saut³³, Corriene Sept³⁴, Marine Germain^{13

14

16}, Renae L Judy^{35

36}, Kerri L Wiggins⁵, Darae Ko^{2

37}, Christopher J O'Donnell^{18

38}, Kent D Taylor³⁹, Franco Giulianini⁷, Mariza De Andrade⁹, Therese H Nøst¹⁰, Anne Boland^{15

16}, Jean-Philippe Empana^{40

41}, Satoshi Koyama^{17

19

20}, Thomas Gilliland^{18

19

20}, Ron Do^{22

23

42}, Jennifer E Huffman⁴³, Xin Wang²⁶, Wei Zhou⁴⁴, Jose Manuel Soria¹², Juan Carlos Souto^{12

45}, Nathan Pankratz⁴⁶, Jeffery Haessler³⁰, Kristian Hindberg³¹, Frits R Rosendaal³⁶, Constance Turman³⁴, Robert Olaso^{15

16}, Rachel L Kember⁴⁷, Traci M Bartz⁴⁸, Julie A Lynch⁴⁹, Susan R Heckbert⁵⁰, Sebastian M Armasu⁹, Ben Brumpton¹⁰, David M Smadja^{51

52}, Xavier Jouven^{53

54}, Issei Komuro⁵⁵, Katharine R Clapham^{56

18

20}, Ruth J F Loos²², Cristen J Willer²⁷, Maria Sabater-Lleal^{12

57}, James S Pankow²¹, Alexander P Reiner^{30

50}, Vania M Morelli^{31

32}, Paul M Ridker^{7

8}, Astrid van Hylckama Vlieg³⁶, Jean-François Deleuze^{15

16

58}, Peter Kraft³⁴, Daniel J Rader^{6

59}; Global Biobank Meta-Analysis Initiative; Estonian Biobank Research Team; 23andMe Research Team; Biobank Japan; CHARGE Hemostasis Working Group; Kyung Min Lee⁶⁰, Bruce M Psaty^{5

61

50}, Anne Heidi Skogholt¹⁰, Joseph Emmerich^{62

63}, Pierre Suchon^{33

64}, Stephen S Rich⁶⁵, Ha My T Vy^{22

23}, Weihong Tang²¹, Rebecca D Jackson⁶⁶, John-Bjarne Hansen^{31

32}, Pierre-Emmanuel Morange^{33

64}, Christopher Kabrhel^{67

68}, David-Alexandre Trégouët^#^{13

14

16}, Scott M Damrauer^#^{35

59

69}, Andrew D Johnson^#^{1

2}, Nicholas L Smith^#^{50

70

71}

Affiliations

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.).

^# Contributed equally.

PMID: 36154123
PMCID: PMC10152894
DOI: 10.1161/CIRCULATIONAHA.122.059675

Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors

Florian Thibord et al. Circulation. 2022.

. 2022 Oct 18;146(16):1225-1242.

doi: 10.1161/CIRCULATIONAHA.122.059675. Epub 2022 Sep 26.

Authors

Affiliations

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.).

^# Contributed equally.

PMID: 36154123
PMCID: PMC10152894
DOI: 10.1161/CIRCULATIONAHA.122.059675

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.

Keywords: genetics; genome-wide association study; meta-analysis; venous thromboembolism; venous thrombosis.

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Conflict of interest statement

Conflict of Interest Disclosures

B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. P.M.R. has received investigator initiated research grant support for unrelated projects from NHLBI, Operation Warp Speed, Novartis, Kowa, Amarin, and Pfizer; and has served as a consultant on unrelated issues to Novo Nordisk, Flame, Agepha, Uppton, Novartis, Jansen, Health Outlook, Civi Biopharm, Alnylam, and SOCAR. P.N. reports investigator-initated grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Novartis, Roche / Genentech, is a co-founder of TenSixteen Bio, is a scientific advisory board member of Esperion Therapeutics, geneXwell, and TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. D.C. has received research funding for unrelated projects from Pfizer. D.Ko initiated research grant from Boston Scientific, Consulting fee from Eagle Pharmaceutical, both unrelated to the current work. C.J.O. is employed by Novartis Institute of Biomedical Research. G.C-P. and X.W. are employed by and hold stock or stock options in 23andMe, Inc. The spouse of C.J.W. works at Regeneron Pharmaceuticals. K.R.C. reports fees from Tectonics Therapeutics. R.L-G. is contractor of Metabolon, Inc. R.D. reported receiving grants from AstraZeneca, grants and non-financial support from Goldfinch Bio, being a scientific co-founder, consultant and equity holder for Pensieve Health (pending), and being a consultant for Variant Bio, all not related to this work. D.Klarin is a scientific advisor and received consulting fees from Bitterroot Bio, Inc unrelated to the current research. S.M.D. receives research support from RenalytixAI and personal consulting fees from Calico Labs, outside the scope of the current research. S.M.D. is named as a co-inventor on a Government-owned US Patent application related to the use of genetic risk prediction for venous thromboembolic disease filed by the US Department of Veterans Affairs in accordance with Federal regulatory requirements. All other authors had nothing to disclose.

Figures

**Figure 1:. Analyses Workflow**
Workflow of genetic analyses conducted for this study.

**Figure 2:. Genetic loci associated with VTE**
This figure presents the 135 loci significantly associated with VTE identified across all 4 meta-analyses: the Discovery (in red), the overall meta-analysis (in green), the analysis restricted to individuals of European ancestry (in purple), African ancestry (in orange) and Hispanic ancestry (in blue). Novel loci are represented with circles and known loci with diamonds. Loci with replication evidence are indicated with a red ‘*’.

**Figure 3:. Genetic risk score analysis**
Distribution of the GRS in VTE cases (in green) and controls (in purple) as a density plot (A) and a boxplot (B). (C) Presentation of the VTE risk as odds ratios and associated 95% confidence intervals (y-axis) for different percentiles ranges of the GRS score (x-axis) relative to the middle range (45–55%).

**Figure 4:. Significant associations of protein QTL Mendelian Randomization**
23 proteins significantly associated with VTE, out of 1,216 plasma protein analyzed, using the combined VTE summary statistics.

**Figure 5:. VTE genetic loci shared with hemostatic factors and blood traits**
(A) Number of VTE loci shared with each of the 10 hemostatic factors investigated. Loci with shared variants that had an opposite effect direction between the trait and VTE are indicated in orange, while those that had the same effect direction are presented in blue. Loci with multiple independent shared variants and conflictual effect directions are indicated in gray. (B) Same analysis with complete blood count traits: PLT (platelet count), MPV (mean platelet volume), RBC (red blood cell count), MCV (mean corpuscular volume), HCT (hematocrit), MCH (mean corpuscular hemoglobin), MCHC (MCH concentration), HGB (hemoglobin concentration), RDW (red cell distribution width), WBC (white blood cell count), MONO (monocyte count), NEU (neutrophil count), EOS (eosinophil count), BASO (basophil count), LYM (lymphocyte count).

**Figure 6:. PheWAS traits sharing at least 10 loci with VTE**
This figure presents the pheWAS traits sharing at least 10 loci with VTE. Shape and color represent one of 5 categories: Complete Blood Count (CBC) traits, lipid traits, liver enzyme, height and weight traits, or other (if the trait did not fit in one of the aforementioned categories). The x-axis indicates the number of loci shared between VTE and the pheWAS trait, while the y-axis indicates the proportion of loci where the direction of effect was the same between the pheWAS trait and VTE. As a result, traits close to 100% have the same direction of effect than VTE at most shared loci, while traits close to 0% have an opposite direction than VTE at most shared loci.

See this image and copyright information in PMC

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Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors

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Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors

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