Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors
Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors
ABSTRACT Venous thromboembolism (VTE) is a complex disease with environmental and genetic determinants. We present new cross-ancestry meta-analyzed genome-wide association study (GWAS) results from 30 studies, with replication of novel loci and their characterization through in silico genomic interrogations. In our initial genetic discovery effort that included 55,330 participants with VTE (47,822 European, 6,320 African, and 1,188 Hispanic ancestry), we identified 48 novel associations of which 34 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. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein QTL Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 novel GWAS loci provided insights to biological pathways contributing to VTE, indicating that some loci may contribute to VTE through well-characterized coagulation pathways while others provide 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. In summary, these findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of antithrombosis treatments with reduced risk of bleeds.
Brumpton Ben、Olaso Robert、Morelli Vania M.、Tr¨|gou?t David-Alexandre、Pankow James S.、Estonian Biobank Research Team、Kember Rachel L.、Armasu Sebastian M.、Ko Darae、Taylor Kent D.、Giulianini Franco、N?st Therese H.、Empana Jean-Philippe、Koyama Satoshi、Soria Jose Manuel、Souto Juan Carlos、Tang Weihong、Hansen John-Bjarne、Morange Pierre-Emmanuel、Damrauer Scott、Smith Nicholas L.、Willer Cristen、Reiner Alexander P.、Deleuze Jean-Fran?ois、Kraft Peter、Rader Daniel J.、McKnight Barbara、Lee Kyung Min、Psaty Bruce M.、Emmerich Joseph、Suchon Pierre、De Andrade Mariza、Chen Ming-Huei、Chasman Daniel I.、Goode Ellen L.、Hveem Kristian、Teder-Laving Maris、Martinez-Perez Angel、A?ssi Dylan、Natarajan Pradeep、Nadkarni Girish N.、Kooperberg Charles、Braekkan Sigrid K.、Ito Kaoru、Boland Anne、Johnson Andrew D.、Daian-Bacq Delphine、Wiggins Kerri L.、Jouven Xavier、Haessler Jeffery、Lynch Julie A.、Bartz Traci M.、Judy Renae L.、Japan Biobank、Germain Marine、Li-Gao Ruifang、Jackson Rebecca D.、Loos Ruth J.F.、Skogholt Anne Heidi、Global Biobank Meta-Analysis Initiative、van Hylckama Vlieg Astrid、Kabrhel Christopher、Pankratz Nathan、23andMe Research Team、Levin Michael G.、Cuellar-Partida Gabriel、Sept Corriene、Smadja David M.、Heckbert Susan R.、Sabater-Lleal Maria、Turman Constance、Lutsey Pamela L.、Thibord Florian、Komuro Issei、Ridker Paul M.、Wolford Brooke N.、Saut Noemie、Rich Stephen S.、Wang Xin、Clapham Katharine、Klarin Derek、O?ˉDonnell Christopher、Brody Jennifer A.、Pattee Jack W.、Gilliland Thomas、Hindberg Kristian、Zhou Wei、Rosendaal Frits R.、Vy Ha My T.、Do Ron
K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and TechnologyCentre National de Recherche en G¨|nomique Humaine, CEA, Universit¨| Paris-Saclay||Laboratory of Excellence on Medical GenomicsThrombosis Research Center (TREC), UiT - The Arctic University of Norway||Division of internal medicine, University Hospital of North NorwayBordeaux Population Health Research Center, University of Bordeaux||UMR1219, INSERM||Laboratory of Excellence on Medical GenomicsDivision of Epidemiology and Community Health, University of MinnesotaPsychiatry, University of PennsylvaniaDepartment of Quantitative Health Sciences, Mayo ClinicSection of Cardiovascular Medicine, Boston University School of Medicine||The Framingham Heart Study, Boston University and NHLBIInstitute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical InnovationDivision of Preventive Medicine, Brigham and Women?ˉs HospitalK.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and TechnologyIntegrative Epidemiology of cardiovascular diseases, Universit¨| Paris Descartes, Sorbonne Paris Cit¨|||Paris Cardiovascular Research Center, Inserm U970, Universit¨| Paris Descartes, Sorbonne Paris Cit¨|Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences||Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard & MIT||Cardiovascular Research Center, Massachusetts General HospitalGenomics of Complex Disease Unit, Sant Pau Biomedical Research Institute (IIB Sant Pau) St Quinti 77-79Unit of Thrombosis and Hemostasis, Hospital de la Santa Creu i Sant Pau||Genomics of Complex Disease Unit, Sant Pau Biomedical Research Institute (IIB Sant Pau) St Quinti 77-79Division of Epidemiology and Community Health, University of MinnesotaThrombosis Research Center (TREC), UiT - The Arctic University of Norway||Division of internal medicine, University Hospital of North NorwayHematology Laboratory, La Timone University Hospital of Marseille||C2VN, INSERM, INRAE, Aix-Marseille UniversityMedicine, Copora Michael J. Crescenz Philadelphia VA Medical CenterCardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington||Department of Surgery, Perelman School of Medicine University of PennsylvaniaDepartment of Computational Medicine and Bioinformatics, University of MichiganDepartment of Epidemiology, University of Washington||Division of Public Health Sciences, Fred Hutchinson Cancer Research CenterCentre National de Recherche en G¨|nomique Humaine, CEA, Universit¨| Paris-Saclay||Centre D?ˉEtude du Polymorphisme Humain, Fondation Jean Dausset||Laboratory of Excellence on Medical GenomicsDepartment of Epidemiology, Harvard TH Chan Harvard School of Public HealthCardiology, Medical Genetics, University of PennsylvaniaCardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of WashingtonVA Informatics & Computing Infrastructure, VA Salt Lake City Healthcare SystemCardiovascular Health Research Unit, Department of Medicine, University of Washington||Department of Epidemiology, University of Washington||Department of Health Systems and Population Heath, University of WashingtonDepartment of vascular medicine, Paris Saint-Joseph Hospital Group, University of Paris||UMR1153, INSERM CRESSHematology Laboratory, La Timone University Hospital of Marseille||C2VN, INSERM, INRAE, Aix-Marseille UniversityDepartment of Quantitative Health Sciences, Mayo ClinicPopulation Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute||The Framingham Heart Study, Boston University and NHLBIDivision of Preventive Medicine, Brigham and Women?ˉs Hospital||Harvard Medical SchoolDepartment of Quantitative Health Sciences, Mayo ClinicHUNT Research Center, Department of Public Health and Nursing, Norwegian University of Science and Technology||K.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and TechnologyInstitute of Genomics, University of TartuGenomics of Complex Disease Unit, Sant Pau Biomedical Research Institute (IIB Sant Pau) St Quinti 77-79Bordeaux Population Health Research Center, University of Bordeaux||UMR1219, INSERMCardiovascular Research Center, Massachusetts General Hospital||Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard & MIT||Department of Medicine, Harvard Medical School, Shattuck StThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai||Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai||Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount SinaiDivision of Public Health Sciences, Fred Hutchinson Cancer Research CenterThrombosis Research Center (TREC), UiT - The Arctic University of Norway||Division of internal medicine, University Hospital of North NorwayLaboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical SciencesCentre National de Recherche en G¨|nomique Humaine, CEA, Universit¨| Paris-Saclay||Laboratory of Excellence on Medical GenomicsPopulation Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute||The Framingham Heart Study, Boston University and NHLBICentre National de Recherche en G¨|nomique Humaine, CEA, Universit¨| Paris-Saclay||Laboratory of Excellence on Medical GenomicsCardiovascular Health Research Unit, Department of Medicine, University of WashingtonIntegrative Epidemiology of cardiovascular diseases, Universit¨| Paris Descartes, Sorbonne Paris Cit¨|||Paris Cardiovascular Research Center, Inserm U970, Universit¨| Paris Descartes, Sorbonne Paris Cit¨|Division of Public Health Sciences, Fred Hutchinson Cancer Research CenterVA Informatics & Computing Infrastructure, VA Salt Lake City Healthcare System||Epidemiology, University of UtahCardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of WashingtonSurgery, University of PennsylvaniaInstitute of Medical Science, University of TokyoBordeaux Population Health Research Center, University of Bordeaux||UMR1219, INSERM||Laboratory of Excellence on Medical GenomicsClinical Epidemiology, Leiden University Medical CenterCollege of Medicine, Ohio State UniversityThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount SinaiK.G. Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and TechnologyClinical Epidemiology, Leiden University Medical CenterEmergency Medicine, Massachusetts General Hospital||Emergency Medicine, Harvard Medical SchoolDepartment of Laboratory Medicine and Pathology, University of MinnesotaDivision of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania||Medicine, Copora Michael J. Crescenz Philadelphia VA Medical Center23andMe, Inc.Department of Epidemiology, Harvard TH Chan Harvard School of Public HealthHematology Department and Biosurgical Research Lab (Carpentier Foundation), European Georges Pompidou Hospital, Assistance Publique H?pitaux de Paris||Innovative Therapies in Haemostasis, INSERM, Universit¨| de ParisDepartment of Epidemiology, University of WashingtonGenomics of Complex Disease Unit, Sant Pau Biomedical Research Institute (IIB Sant Pau) St Quinti 77-79||Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular MedicineDepartment of Epidemiology, Harvard TH Chan Harvard School of Public HealthDivision of Epidemiology and Community Health, University of MinnesotaPopulation Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute||The Framingham Heart Study, Boston University and NHLBIDepartment of Cardiovascular Medicine, University of TokyoDivision of Preventive Medicine, Brigham and Women?ˉs Hospital||Harvard Medical SchoolDepartment of Computational Medicine and Bioinformatics, University of MichiganHematology Laboratory, La Timone University Hospital of MarseilleCenter for Public Health Genomics, University of Virginia23andMe, Inc.Division of Cardiovascular Medicine, Brigham & Women?ˉs Hospital||Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard & MIT||Department of Medicine, Harvard Medical School, Shattuck StDivision of Vascular Surgery, Stanford University School of MedicineCardiology, VA Boston Healthcare SystemCardiovascular Health Research Unit, Department of Medicine, University of WashingtonDivision of Biostatistics, University of Minnesota||Center for Innovative Design & Analysis and Department of Biostatistics & Informatics, Colorado School of Public HealthCardiovascular Research Center, Massachusetts General Hospital||Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard & MIT||Department of Medicine, Harvard Medical School, Shattuck StThrombosis Research Center (TREC), UiT - The Arctic University of NorwayAnalytic and Translational Genetics Unit, Department of Medicine, Massachusetts General HospitalClinical Epidemiology, Leiden University Medical CenterThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai||Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai||Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai||BioMe Phenomics Center, Icahn School of Medicine at Mount Sinai
基础医学生物科学研究方法、生物科学研究技术遗传学
venous thrombosisvenous thromboembolismgeneticgenome-wide association studiestranscriptome-wide association study
Brumpton Ben,Olaso Robert,Morelli Vania M.,Tr¨|gou?t David-Alexandre,Pankow James S.,Estonian Biobank Research Team,Kember Rachel L.,Armasu Sebastian M.,Ko Darae,Taylor Kent D.,Giulianini Franco,N?st Therese H.,Empana Jean-Philippe,Koyama Satoshi,Soria Jose Manuel,Souto Juan Carlos,Tang Weihong,Hansen John-Bjarne,Morange Pierre-Emmanuel,Damrauer Scott,Smith Nicholas L.,Willer Cristen,Reiner Alexander P.,Deleuze Jean-Fran?ois,Kraft Peter,Rader Daniel J.,McKnight Barbara,Lee Kyung Min,Psaty Bruce M.,Emmerich Joseph,Suchon Pierre,De Andrade Mariza,Chen Ming-Huei,Chasman Daniel I.,Goode Ellen L.,Hveem Kristian,Teder-Laving Maris,Martinez-Perez Angel,A?ssi Dylan,Natarajan Pradeep,Nadkarni Girish N.,Kooperberg Charles,Braekkan Sigrid K.,Ito Kaoru,Boland Anne,Johnson Andrew D.,Daian-Bacq Delphine,Wiggins Kerri L.,Jouven Xavier,Haessler Jeffery,Lynch Julie A.,Bartz Traci M.,Judy Renae L.,Japan Biobank,Germain Marine,Li-Gao Ruifang,Jackson Rebecca D.,Loos Ruth J.F.,Skogholt Anne Heidi,Global Biobank Meta-Analysis Initiative,van Hylckama Vlieg Astrid,Kabrhel Christopher,Pankratz Nathan,23andMe Research Team,Levin Michael G.,Cuellar-Partida Gabriel,Sept Corriene,Smadja David M.,Heckbert Susan R.,Sabater-Lleal Maria,Turman Constance,Lutsey Pamela L.,Thibord Florian,Komuro Issei,Ridker Paul M.,Wolford Brooke N.,Saut Noemie,Rich Stephen S.,Wang Xin,Clapham Katharine,Klarin Derek,O?ˉDonnell Christopher,Brody Jennifer A.,Pattee Jack W.,Gilliland Thomas,Hindberg Kristian,Zhou Wei,Rosendaal Frits R.,Vy Ha My T.,Do Ron.Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors[EB/OL].(2025-03-28)[2025-06-09].https://www.medrxiv.org/content/10.1101/2022.03.04.22271003.点此复制
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