Stroke genetics informs drug discovery and risk prediction across ancestries.

Autor:	Mishra A; Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France., Malik R; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany., Hachiya T; Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan., Jürgenson T; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.; Institute of Mathematics and Statistics, University of Tartu, Tartu, Estonia., Namba S; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan., Posner DC; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Kamanu FK; TIMI Study Group, Boston, MA, USA.; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Koido M; Division of Molecular Pathology, Institute of Medical Sciences, The University of Tokyo, Tokyo, Japan.; Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan., Le Grand Q; Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France., Shi M; Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan., He Y; Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan., Georgakis MK; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, MA, USA., Caro I; Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France., Krebs K; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia., Liaw YC; Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.; Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, Taiwan., Vaura FC; Department of Internal Medicine, University of Turku, Turku, Finland.; Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Turku, Finland., Lin K; Nuffield Department of Population Health, University of Oxford, Oxford, UK., Winsvold BS; Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.; K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.; Department of Neurology, Oslo University Hospital, Oslo, Norway., Srinivasasainagendra V; Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA., Parodi L; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, MA, USA., Bae HJ; Department of Neurology and Cerebrovascular Disease Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea., Chauhan G; Rajendra Institute of Medical Sciences, Ranchi, India., Chong MR; Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada.; Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada., Tomppo L; Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland., Akinyemi R; Center for Genomic and Precision Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria.; Neuroscience and Ageing Research Unit Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria., Roshchupkin GV; Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands., Habib N; The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel., Jee YH; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Thomassen JQ; Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark., Abedi V; Department of Molecular and Functional Genomics, Weis Center for Research, Geisinger Health System, Danville, VA, USA.; Department of Public Health Sciences, College of Medicine, The Pennsylvania State University, State College, PA, USA., Cárcel-Márquez J; Stroke Pharmacogenomics and Genetics Laboratory, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.; Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain., Nygaard M; The Danish Twin Registry, Department of Public Health, University of Southern Denmark, Odense, Denmark.; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark., Leonard HL; Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD, USA.; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; Data Tecnica International, Glen Echo, MD, USA., Yang C; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA., Yonova-Doing E; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; Department of Genetics, Novo Nordisk Research Centre Oxford, Oxford, UK., Knol MJ; Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands., Lewis AJ; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA., Judy RL; Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA., Ago T; Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Amouyel P; University of Lille, INSERM U1167, RID-AGE, LabEx DISTALZ, Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France.; CHU Lille, Public Health Department, Lille, France.; Institut Pasteur de Lille, Lille, France., Armstrong ND; Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA., Bakker MK; UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands., Bartz TM; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.; Department of Biostatistics, University of Washington, Seattle, WA, USA., Bennett DA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA., Bis JC; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA., Bordes C; Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France., Børte S; K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.; Research and Communication Unit for Musculoskeletal Health (FORMI), Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway., Cain A; The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel., Ridker PM; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Cho K; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Chen Z; Nuffield Department of Population Health, University of Oxford, Oxford, UK.; MRC Population Health Research Unit, University of Oxford, Oxford, UK., Cruchaga C; Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, Saint Louis, MO, USA., Cole JW; VA Maryland Health Care System, Baltimore, MD, USA.; Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA., de Jager PL; Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, MA, USA.; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA., de Cid R; GenomesForLife-GCAT Lab Group, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain., Endres M; Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Center for Stroke Research Berlin, Berlin, Germany.; German Center for Neurodegenerative Diseases (DZNE), partner site Berlin, Berlin, Germany.; German Centre for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany., Ferreira LE; Post-Graduation Program on Health and Environment, Department of Medicine and Joinville Stroke Biobank, University of the Region of Joinville, Santa Catarina, Brazil., Geerlings MI; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Gasca NC; Department of Biostatistics, University of Washington, Seattle, WA, USA., Gudnason V; Icelandic Heart Association, Kopavogur, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Hata J; Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., He J; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA., Heath AK; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK., Ho YL; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Havulinna AS; Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.; Institute for Molecular Medicine Finland, FIMM-HiLIFE, Helsinki, Finland., Hopewell JC; Clinical Trial Service and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK., Hyacinth HI; Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA., Inouye M; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK., Jacob MA; Department of Neurology, Donders Center for Medical Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands., Jeon CE; Los Angeles County Department of Public Health, Los Angeles, CA, USA., Jern C; Institute of Biomedicine, Department of Laboratory Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.; Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden., Kamouchi M; Department of Health Care Administration and Management, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Keene KL; Department of Biology, Brody School of Medicine Center for Health Disparities, East Carolina University, Greenville, NC, USA., Kitazono T; Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Kittner SJ; Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.; Department of Neurology and Geriatric Research and Education Clinical Center, VA Maryland Health Care System, Baltimore, MD, USA., Konuma T; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan., Kumar A; Rajendra Institute of Medical Sciences, Ranchi, India., Lacaze P; Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia., Launer LJ; Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA., Lee KJ; Department of Neurology, Korea University Guro Hospital, Seoul, Republic of Korea., Lepik K; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.; Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.; Swiss Institute of Bioinformatics, Lausanne, Switzerland.; University Center for Primary Care and Public Health, Lausanne, Switzerland., Li J; Department of Molecular and Functional Genomics, Weis Center for Research, Geisinger Health System, Danville, VA, USA., Li L; Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China., Manichaikul A; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Markus HS; Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Marston NA; TIMI Study Group, Boston, MA, USA.; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Meitinger T; Institute of Human Genetics, Technical University of Munich, Munich, Germany.; Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany., Mitchell BD; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.; Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA., Montellano FA; Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany.; Department of Neurology, University Hospital Würzburg, Würzburg, Germany., Morisaki T; Division of Molecular Pathology, Institute of Medical Sciences, The University of Tokyo, Tokyo, Japan., Mosley TH; The MIND Center, University of Mississippi Medical Center, Jackson, MS, USA., Nalls MA; Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD, USA.; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; Data Tecnica International, Glen Echo, MD, USA., Nordestgaard BG; Department of Clinical Biochemistry, Copenhagen University Hospital-Herlev and Gentofte, Copenhagen, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., O'Donnell MJ; College of Medicine Nursing and Health Science, NUI Galway, Galway, Ireland., Okada Y; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.; Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.; Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Japan., Onland-Moret NC; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Ovbiagele B; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA., Peters A; Institute of Epidemiology, Helmholtz Zentrum München,, German Research Center for Environmental Health, Neuherberg, Germany.; Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig Maximilian University Munich, Munich, Germany.; German Centre for Cardiovascular Research (DZHK), partner site Munich, Munich, Germany., Psaty BM; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.; Department of Epidemiology, University of Washington, Seattle, WA, USA.; Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA., Rich SS; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Rosand J; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, MA, USA.; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA., Sabatine MS; TIMI Study Group, Boston, MA, USA.; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Sacco RL; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.; Evelyn F. McKnight Brain Institute, Gainesville, FL, USA., Saleheen D; Division of Cardiology, Department of Medicine, Columbia University, New York, NY, USA., Sandset EC; Stroke Unit, Department of Neurology, Oslo University Hospital, Oslo, Norway.; Research and Development, The Norwegian Air Ambulance Foundation, Oslo, Norway., Salomaa V; Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland., Sargurupremraj M; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA., Sasaki M; Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan., Satizabal CL; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA.; Framingham Heart Study, Framingham, MA, USA., Schmidt CO; University Medicine Greifswald, Institute for Community Medicine, SHIP/KEF, Greifswald, Germany., Shimizu A; Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan., Smith NL; Department of Epidemiology, University of Washington, Seattle, WA, USA.; Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA.; Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, WA, USA., Sloane KL; Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA., Sutoh Y; Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan., Sun YV; Atlanta VA Health Care System, Decatur, GA, USA.; Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA., Tanno K; Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan., Tiedt S; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany., Tatlisumak T; Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Unviersity Hospital, Gothenburg, Sweden., Torres-Aguila NP; Stroke Pharmacogenomics and Genetics Laboratory, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain., Tiwari HK; Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA., Trégouët DA; Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France., Trompet S; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands., Tuladhar AM; Department of Neurology, Donders Center for Medical Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands., Tybjærg-Hansen A; Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., van Vugt M; Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Vibo R; Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia., Verma SS; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA., Wiggins KL; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA., Wennberg P; Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden., Woo D; Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA., Wilson PWF; Atlanta VA Health Care System, Decatur, GA, USA.; Department of Medicine, Division of Cardiovascular Disease, Emory University School of Medicine, Atlanta, GA, USA., Xu H; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA., Yang Q; Framingham Heart Study, Framingham, MA, USA.; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA., Yoon K; Division of Genome Science, Department of Precision Medicine, National Institute of Health, Cheongju, Republic of Korea., Millwood IY; Nuffield Department of Population Health, University of Oxford, Oxford, UK.; MRC Population Health Research Unit, University of Oxford, Oxford, UK., Gieger C; Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany., Ninomiya T; Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Grabe HJ; Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.; German Center for Neurodegenerative Diseases (DZNE), site Rostock/Greifswald, Rostock, Germany., Jukema JW; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.; Netherlands Heart Institute, Utrecht, The Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands., Rissanen IL; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Strbian D; Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland., Kim YJ; Division of Genome Science, Department of Precision Medicine, National Institute of Health, Cheongju, Republic of Korea., Chen PH; Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, Taiwan., Mayerhofer E; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, MA, USA., Howson JMM; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; Department of Genetics, Novo Nordisk Research Centre Oxford, Oxford, UK., Irvin MR; Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA., Adams H; Department of Clinical Genetics, Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.; Latin American Brain Health (BrainLat), Universidad Adolfo Ibáñez, Santiago, Chile., Wassertheil-Smoller S; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA., Christensen K; The Danish Twin Registry, Department of Public Health, University of Southern Denmark, Odense, Denmark.; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark., Ikram MA; Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands., Rundek T; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.; Evelyn F. McKnight Brain Institute, Gainesville, FL, USA., Worrall BB; Department of Neurology, University of Virginia, Charlottesville, VA, USA.; Department of Public Health Science, University of Virginia, Charlottesville, VA, USA., Lathrop GM; McGill Genome Centre, Montreal, Quebec, Canada., Riaz M; Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia., Simonsick EM; Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA., Kõrv J; Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia., França PHC; Post-Graduation Program on Health and Environment, Department of Medicine and Joinville Stroke Biobank, University of the Region of Joinville, Santa Catarina, Brazil., Zand R; Geisinger Neuroscience Institute, Geisinger Health System, Danville, PA, USA.; Department of Neurology, College of Medicine, The Pennsylvania State University, State College, PA, USA., Prasad K; Rajendra Institute of Medical Sciences, Ranchi, India., Frikke-Schmidt R; Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., de Leeuw FE; Department of Neurology, Donders Center for Medical Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands., Liman T; Center for Stroke Research Berlin, Berlin, Germany.; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Klinik für Neurologie, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany., Haeusler KG; Department of Neurology, University Hospital Würzburg, Würzburg, Germany., Ruigrok YM; UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands., Heuschmann PU; Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany.; Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany.; Clinical Trial Center, University Hospital Würzburg, Würzburg, Germany., Longstreth WT; Department of Epidemiology, University of Washington, Seattle, WA, USA.; Department of Neurology, University of Washington, Seattle, WA, USA., Jung KJ; Nuffield Department of Population Health, University of Oxford, Oxford, UK.; Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Republic of Korea., Bastarache L; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA., Paré G; Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada.; Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada.; Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada., Damrauer SM; Department of Surgery and Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.; Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA., Chasman DI; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Rotter JI; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA., Anderson CD; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, MA, USA.; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA.; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA., Zwart JA; Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.; K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway., Niiranen TJ; Department of Internal Medicine, University of Turku, Turku, Finland.; Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Turku, Finland.; Division of Medicine, Turku University Hospital, Turku, Finland., Fornage M; Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA., Liaw YP; Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, Taiwan.; Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung, Taiwan., Seshadri S; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA.; Framingham Heart Study, Framingham, MA, USA.; Department of Neurology, Boston University School of Medicine, Boston, MA, USA., Fernández-Cadenas I; Stroke Pharmacogenomics and Genetics Laboratory, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain., Walters RG; Nuffield Department of Population Health, University of Oxford, Oxford, UK.; MRC Population Health Research Unit, University of Oxford, Oxford, UK., Ruff CT; TIMI Study Group, Boston, MA, USA.; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Owolabi MO; Center for Genomic and Precision Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria.; Department of Medicine, University of Ibadan, Ibadan, Nigeria., Huffman JE; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Milani L; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia., Kamatani Y; Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan., Dichgans M; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany. Martin.Dichgans@med.uni-muenchen.de.; Munich Cluster for Systems Neurology, Munich, Germany. Martin.Dichgans@med.uni-muenchen.de.; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. Martin.Dichgans@med.uni-muenchen.de., Debette S; Bordeaux Population Health Research Center, University of Bordeaux, Inserm, UMR 1219, Bordeaux, France. stephanie.debette@u-bordeaux.fr.; Department of Neurology, Institute for Neurodegenerative Diseases, CHU de Bordeaux, Bordeaux, France. stephanie.debette@u-bordeaux.fr.
Jazyk:	angličtina
Zdroj:	Nature [Nature] 2022 Nov; Vol. 611 (7934), pp. 115-123. Date of Electronic Publication: 2022 Sep 30.
DOI:	10.1038/s41586-022-05165-3
Abstrakt:	Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries. (© 2022. The Author(s).)
Databáze:	MEDLINE
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