Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke

doi:10.1212/WNL.0000000000201006

Meta-Analysis

. 2022 Oct 17;99(16):e1738-e1754.

doi: 10.1212/WNL.0000000000201006.

Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke

Thomas Jaworek¹, Huichun Xu¹, Brady J Gaynor¹, John W Cole¹, Kristiina Rannikmae¹, Tara M Stanne¹, Liisa Tomppo¹, Vida Abedi¹, Philippe Amouyel¹, Nicole D Armstrong¹, John Attia¹, Steven Bell¹, Oscar R Benavente¹, Giorgio B Boncoraglio¹, Adam Butterworth¹; Cervical Artery Dissections and Ischemic Stroke Patients (CADSIP) Consortium; Jara Carcel-Marquez¹, Zhengming Chen¹, Michael Chong¹, Carlos Cruchaga¹, Mary Cushman¹, John Danesh¹, Stéphanie Debette¹, David J Duggan¹, Jon Peter Durda¹, Gunnar Engstrom¹, Chris Enzinger¹, Jessica D Faul¹, Natalie S Fecteau¹, Israel Fernandez-Cadenas¹, Christian Gieger¹, Anne-Katrin Giese¹, Raji P Grewal¹, Ulrike Grittner¹, Aki S Havulinna¹, Laura Heitsch¹, Marc C Hochberg¹, Elizabeth Holliday¹, Jie Hu¹, Andreea Ilinca¹; INVENT Consortium; Marguerite R Irvin¹, Rebecca D Jackson¹, Mina A Jacob¹, Raquel Rabionet¹, Jordi Jimenez-Conde¹, Julie A Johnson¹, Yoichiro Kamatani¹, Sharon L R Kardia¹, Masaru Koido¹, Michiaki Kubo¹, Leslie Lange¹, Jin-Moo Lee¹, Robin Lemmens¹, Christopher R Levi¹, Jiang Li¹, Liming Li¹, Kuang Lin¹, Haley Lopez¹, Sothear Luke¹, Jane Maguire¹, Patrick F McArdle¹, Caitrin W McDonough¹, James F Meschia¹, Tiina Metso¹, Martina Müller-Nurasyid¹, Timothy D O'Connor¹, Martin O'Donnell¹, Leema R Peddareddygari¹, Joanna Pera¹, James A Perry¹, Annette Peters¹, Jukka Putaala¹, Debashree Ray¹, Kathryn Rexrode¹, Marta Ribases¹, Jonathan Rosand¹, Peter M Rothwell¹, Tatjana Rundek¹, Kathleen A Ryan¹, Ralph L Sacco¹, Veikko Salomaa¹, Cristina Sanchez-Mora¹, Reinhold Schmidt¹, Pankaj Sharma¹, Agnieszka Slowik¹, Jennifer A Smith¹, Nicholas L Smith¹, Sylvia Wassertheil-Smoller¹, Martin Söderholm¹, O Colin Stine¹, Daniel Strbian¹, Cathie L M Sudlow¹, Turgut Tatlisumak¹, Chikashi Terao¹, Vincent Thijs¹, Nuria P Torres-Aguila¹, David-Alexandre Trégouët¹, Anil M Tuladhar¹, Jan H Veldink¹, Robin G Walters¹, David R Weir¹, Daniel Woo¹, Bradford B Worrall¹, Charles C Hong¹, Owen A Ross¹, Ramin Zand¹, Frank-Erik de Leeuw¹, Arne G Lindgren¹, Guillaume Pare¹, Christopher D Anderson¹, Hugh S Markus¹, Christina Jern¹, Rainer Malik¹, Martin Dichgans¹, Braxton D Mitchell², Steven J Kittner¹; Early Onset Stroke Genetics Consortium of the International Stroke Genetics Consortium (ISGC)

Affiliations

¹ From the Division of Endocrinology (T.J., H.X., B.J.G, B.D.M., K.A.R., J.A.P., P.F.M.), Diabetes and Nutrition, Department of Neurology (J.W.C., N.S.F., H.L., S.J.K.), Division of Rheumatology and Clinical Immunology (M.C.H.), Department of Medicine, Department of Epidemiology and Public Health (M.C.H.), and Institute for Genome Sciences (T.D.O.C.), University of Maryland School of Medicine; VA Maryland Health Care System (J.W.C.); Centre for Medical Informatics (K.R., C.L.M.S.), Usher Institute, University of Edinburgh, United Kingdom; Institute of Biomedicine (T.M.S., C.J.), Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Neurology (L.T., J.P., D.S., T.T.), Helsinki University Hospital and University of Helsinki, Finland; Department of Molecular and Functional Genomics (V.A., J.L., R.Z.), Geisinger Health System, Danville, PA; LabEx DISTALZ-U1167 (P.A.), RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, University of Lille; Inserm U1167 (P.A.), Lille; Centre Hospitalier Universitaire Lille (P.A.); Institut Pasteur de Lille (P.A.), France; Department of Epidemiology (N.D.A., M.R.I.), University of Alabama at Birmingham; School of Medicine and Public Health (J.A., E.H.), University of Newcastle and Hunter Medical Research Institute, Australia; Stroke Research Group (S.B., H.S.M.), Department of Clinical Neurosciences, British Heart Foundation Cardiovascular Epidemiology Unit (A.B., J.D.), Department of Public Health and Primary Care, British Heart Foundation Centre of Research Excellence (A.B., J.D.), National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (A.B., J.D.), University of Cambridge (A.B., J.D.), United Kingdom; Department of Neurology (Q.R.B.), University of British Columbia, Vancouver, Canada; Department of Cerebrovascular Diseases (G.B.B.), Fondazione IRCCS Istituto Neurologico "Carlo Besta," Milan, Italy; Health Data Research UK Cambridge (A.B., J.D.); Wellcome Genome Campus (A.B., J.D.), Cambridge, United Kingdom; Stroke Pharmacogenomics and Genetics group (J.C.-M., I.F.-C., N.P.T.-A.), Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain; MRC Population Health Research Unit (Z.C., R.G.W.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Nuffield Department of Clinical Neurosciences (P.M.R.), University of Oxford, United Kingdom; DBCVS Research Institute (M.C., G.P.), Department of Pathology and Molecular Medicine, Population Health Research Institute, McMaster University; Thrombosis & Atherosclerosis Research Institute (TaARI) (M.C., G.P.), Hamilton, Ontario, Canada; Departments of Neurology (J.-M.L.) and Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; Department of Medicine and Laboratory for Clinical Biochemistry Research (J.P.D.), Department of Medicine, (M.C.), University of Vermont Larner College of Medicine, Burlington, VT; Department of Human Genetics (J.D.), Wellcome Sanger Institute, Hinxton, United Kingdom; University of Bordeaux (S.D., D.-A.T.), Inserm, Bordeux Population Health Research Center, UMR 1219; Department of Neurology (S.D.), Institute for Neurodegenerative Disease, Bordeaux University Hospital, France; Quantitative Medicine and Systems Biology Division (D.J.D.), Translational Genomics Research Institute, An Affiliate of City of Hope, Phoenix, AZ; Laboratory for Clinical Biochemistry Research (J.P.D.), Department of Clinical Sciences (G.E., J.A.S., M.S., D.R.W.), Malmö and Department of Clinical Sciences (A.I., M.S., A.G.L.), Neurology, Lund, Lund University, Sweden; Department of Neurology (C.E., R.S.), Medical University Graz, Austria; Survey Research Center (J.D.F.), Institute for Social Research, University of Michigan, Ann Arbor; Stroke Pharmacogenomics and Genetics (I.F.-C.), Fundacio Docència i Recerca MutuaTerrassa, Spain; Unit of Molecular Epidemiology (C.G.), Institute of Epidemiology (C.G., A.P.), Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg; Klinik und Poliklinik für Neurologie (A.-K.G.), Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Germany; Neuroscience Institute (R.P.G., L.R.P.), Saint Francis Medical Center, Trenton, NJ; Department for Biostatistics and Clinical Epidemiology (U.G., ), Charité-University Medical Centre, Berlin, Germany; National Institute for Health and Welfare (A.S.H., V.S.), Helsinki, Finland; Departments of Emergency Medicine and Neurology (L.H.), Washington University School of Medicine, St. Louis, MO; Division of Women's Health (K.R.), Department of Medicine and Department of Neurology (C.D.A.), Brigham and Women's Hospital, Harvard Medical School; Department of Epidemiology (J.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Neurology and Rehabilitation Medicine (A.I.), Skane University Hospital, Lund, Sweden; Division of Endocrinology (R.D.J.), Diabetes and Metabolism, Department of Internal Medicine and the Center for Clinical and Translational Science, The Ohio State University, Columbus; Department of Neurology (M.A.J., A.M.T., F.E.d.L.), Radboud University Medical Center, Donders Medical Center for Neuroscience, Nijmegen, the Netherlands; Department of Genetics, Microbiology and Statistics (R.R.J.), Institute of Biomedicine (IBUB), University of Barcelona; Institut de Recerca Sant Joan de Déu (R.R.J.), Esplugues de Llobregat; Centro de investigación biomédica en red (CIBERER) (R.R.J.); Neurovascular Research Group (NEUVAS) (J.J.-C.), Neurology Department, Institut Hospital del Mar d'Investigacio Medica, Universitat Autonoma de Barcelona, Spain; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (J.A.J., C.W.M.), University of Florida, College of Pharmacy; Division of Cardiovascular Medicine (J.A.J.), College of Medicine, University of Florida, Gainesville; Laboratory of Complex Trait Genomics (Y.K.), Graduate School of Frontier Sciences and Department of Cancer Biology (M.K.), Institute of Medical Science, The University of Tokyo, Japan; Department of Epidemiology (S.L.R.K.), School of Public Health, University of Michigan, Ann Arbor; Department of Cancer Biology (M.K.), RIKEN Center for Integrative Medical Sciences (M.K., C.T.), Yokohama, Japan; Department of Medicine (L.L.), University of Colorado Denver, Anschutz Medical Campus, Aurora, CO; Department of Neurosciences, Experimental Neurology (R.L.), VIB Center, For Brain & Disease Research, KU Leuven-University of Leuven; Department of Neurology (R.L.), University Hospitals Leuven, Belgium; John Hunter Hospital (C.R.L.), Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia and Priority Research Centre for Stroke & Brain Injury, University of Newcastle, NSW, Australia; Peking University Health Science Center (L.L.), Department of Epidemiology and Biostatistics, Peking University, Beijing, China; Department of Neurology (S.L., J.F.M., O.A.R.), Mayo Clinic, Jacksonville, FL; Faculty of Health (J.M.), School of Nursing and Midwifery, University of Technology Sydney, NSW, Australia; Department of Neurology (T.M.), Helsinki University Central Hospital, Helsinki, Finland; Institute of Genetic Epidemiology (M.M.-N.), Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg; Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University Mainz, Germany; Department of Medicine I, Ludwig-Maximilians University Munich, Germany; Department of Medicine (C.C.H.) University of Maryland School of Medicine, Baltimore, MD; Health Research Board Clinical Research Facility (M.O.D.), Geata an Eolais, National University of Ireland, Galway; Department of Neurology (J.P., A.S.), Jagiellonian University, Krakow, Poland; Institute for Medical Information Sciences (A.P.), Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany; Department of Epidemiology (D.R.), Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; Psychiatric Genetics Unit (M.R., C.S.-M.), Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona; Department of Psychiatry (C.S.-M.), Hospital Universitari Vall d'Hebron, Barcelona; Biomedical Network Research Centre on Mental Health (CIBERSAM) (M.R.), Instituto de Salud Carlos III, Madrid; Department of Genetics (M.R.), Microbiology, and Statistics, Faculty of Biology, Universitat de Barcelona, Spain; McCance Center for Brain Health (J.R., C.D.A.), Massachusetts General Hospital; Center for Genomic Medicine (J.R.), MGH; Department of Neurology (J.R.), MGH, Boston; Program in Medical and Population Genetics (J.R.), Broad Institute, Cambridge, MA; Department of Neurology and Evelin F. McKnight Brain Institute (T.R., R.L.S.), Miller School of Medicine, University of Miami, FL; Institute of Cardiovascular Research (P.S.), Royal Holloway University of London, and Ashford and St. Peters Hospital (P.S.), Surrey, United Kingdom; Group Health Research Institute (N.L.S.), Group Health Cooperative; Department of Epidemiology (N.L.S.), University of Washington; Seattle Epidemiologic Research and Information Center (N.L.S.), VA Office of Research and Development, Seattle, WA; Department of Epidemiology and Population Health (S.W.-S.), Albert Einstein College of Medicine, New York; BHF Data Science Centre (C.L.S.), Health Data Research UK, London, United Kingdom; Department of Neurology (T.T.) and Department of Clinical Genetics and Genomics (C.J.), Region Vastra Gotaland, Sahlgrenska University Hospital; Department of Clinical Neuroscience (T.T.), Institute of Neurosciences and Physiology, Sahlgrenska Academy at University of Gothenburg, Sweden; Stroke Theme (V.T.), Florey Institute of Neuroscience and Mental Health, University of Melbourne; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Department of Neurology (J.H.V.), University Medical Center Utrecht Brain Center, Utrecht University, the Netherlands; Department of Neurology and Rehabilitation Medicine (D.W.), University of Cincinnati College of Medicine, OH; Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia School of Medicine, Charlottesville; Section of Neurology (A.G.L.), Skåne University Hospital, Lund, Sweden; Program in Medical and Population Genetics (C.D.A.), Broad Institute of MIT and Harvard, Cambridge, MA; Institute for Stroke and Dementia Research (ISD) (R.M., M.D.), University Hospital, LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (M.D.); German Center for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany; Geriatric Research and Education Clinical Center (B.D.M., S.J.K.), Veterans Administration Medical Center, Baltimore, MD.
² From the Division of Endocrinology (T.J., H.X., B.J.G, B.D.M., K.A.R., J.A.P., P.F.M.), Diabetes and Nutrition, Department of Neurology (J.W.C., N.S.F., H.L., S.J.K.), Division of Rheumatology and Clinical Immunology (M.C.H.), Department of Medicine, Department of Epidemiology and Public Health (M.C.H.), and Institute for Genome Sciences (T.D.O.C.), University of Maryland School of Medicine; VA Maryland Health Care System (J.W.C.); Centre for Medical Informatics (K.R., C.L.M.S.), Usher Institute, University of Edinburgh, United Kingdom; Institute of Biomedicine (T.M.S., C.J.), Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Neurology (L.T., J.P., D.S., T.T.), Helsinki University Hospital and University of Helsinki, Finland; Department of Molecular and Functional Genomics (V.A., J.L., R.Z.), Geisinger Health System, Danville, PA; LabEx DISTALZ-U1167 (P.A.), RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, University of Lille; Inserm U1167 (P.A.), Lille; Centre Hospitalier Universitaire Lille (P.A.); Institut Pasteur de Lille (P.A.), France; Department of Epidemiology (N.D.A., M.R.I.), University of Alabama at Birmingham; School of Medicine and Public Health (J.A., E.H.), University of Newcastle and Hunter Medical Research Institute, Australia; Stroke Research Group (S.B., H.S.M.), Department of Clinical Neurosciences, British Heart Foundation Cardiovascular Epidemiology Unit (A.B., J.D.), Department of Public Health and Primary Care, British Heart Foundation Centre of Research Excellence (A.B., J.D.), National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (A.B., J.D.), University of Cambridge (A.B., J.D.), United Kingdom; Department of Neurology (Q.R.B.), University of British Columbia, Vancouver, Canada; Department of Cerebrovascular Diseases (G.B.B.), Fondazione IRCCS Istituto Neurologico "Carlo Besta," Milan, Italy; Health Data Research UK Cambridge (A.B., J.D.); Wellcome Genome Campus (A.B., J.D.), Cambridge, United Kingdom; Stroke Pharmacogenomics and Genetics group (J.C.-M., I.F.-C., N.P.T.-A.), Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain; MRC Population Health Research Unit (Z.C., R.G.W.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Nuffield Department of Clinical Neurosciences (P.M.R.), University of Oxford, United Kingdom; DBCVS Research Institute (M.C., G.P.), Department of Pathology and Molecular Medicine, Population Health Research Institute, McMaster University; Thrombosis & Atherosclerosis Research Institute (TaARI) (M.C., G.P.), Hamilton, Ontario, Canada; Departments of Neurology (J.-M.L.) and Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; Department of Medicine and Laboratory for Clinical Biochemistry Research (J.P.D.), Department of Medicine, (M.C.), University of Vermont Larner College of Medicine, Burlington, VT; Department of Human Genetics (J.D.), Wellcome Sanger Institute, Hinxton, United Kingdom; University of Bordeaux (S.D., D.-A.T.), Inserm, Bordeux Population Health Research Center, UMR 1219; Department of Neurology (S.D.), Institute for Neurodegenerative Disease, Bordeaux University Hospital, France; Quantitative Medicine and Systems Biology Division (D.J.D.), Translational Genomics Research Institute, An Affiliate of City of Hope, Phoenix, AZ; Laboratory for Clinical Biochemistry Research (J.P.D.), Department of Clinical Sciences (G.E., J.A.S., M.S., D.R.W.), Malmö and Department of Clinical Sciences (A.I., M.S., A.G.L.), Neurology, Lund, Lund University, Sweden; Department of Neurology (C.E., R.S.), Medical University Graz, Austria; Survey Research Center (J.D.F.), Institute for Social Research, University of Michigan, Ann Arbor; Stroke Pharmacogenomics and Genetics (I.F.-C.), Fundacio Docència i Recerca MutuaTerrassa, Spain; Unit of Molecular Epidemiology (C.G.), Institute of Epidemiology (C.G., A.P.), Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg; Klinik und Poliklinik für Neurologie (A.-K.G.), Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Germany; Neuroscience Institute (R.P.G., L.R.P.), Saint Francis Medical Center, Trenton, NJ; Department for Biostatistics and Clinical Epidemiology (U.G., ), Charité-University Medical Centre, Berlin, Germany; National Institute for Health and Welfare (A.S.H., V.S.), Helsinki, Finland; Departments of Emergency Medicine and Neurology (L.H.), Washington University School of Medicine, St. Louis, MO; Division of Women's Health (K.R.), Department of Medicine and Department of Neurology (C.D.A.), Brigham and Women's Hospital, Harvard Medical School; Department of Epidemiology (J.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Neurology and Rehabilitation Medicine (A.I.), Skane University Hospital, Lund, Sweden; Division of Endocrinology (R.D.J.), Diabetes and Metabolism, Department of Internal Medicine and the Center for Clinical and Translational Science, The Ohio State University, Columbus; Department of Neurology (M.A.J., A.M.T., F.E.d.L.), Radboud University Medical Center, Donders Medical Center for Neuroscience, Nijmegen, the Netherlands; Department of Genetics, Microbiology and Statistics (R.R.J.), Institute of Biomedicine (IBUB), University of Barcelona; Institut de Recerca Sant Joan de Déu (R.R.J.), Esplugues de Llobregat; Centro de investigación biomédica en red (CIBERER) (R.R.J.); Neurovascular Research Group (NEUVAS) (J.J.-C.), Neurology Department, Institut Hospital del Mar d'Investigacio Medica, Universitat Autonoma de Barcelona, Spain; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (J.A.J., C.W.M.), University of Florida, College of Pharmacy; Division of Cardiovascular Medicine (J.A.J.), College of Medicine, University of Florida, Gainesville; Laboratory of Complex Trait Genomics (Y.K.), Graduate School of Frontier Sciences and Department of Cancer Biology (M.K.), Institute of Medical Science, The University of Tokyo, Japan; Department of Epidemiology (S.L.R.K.), School of Public Health, University of Michigan, Ann Arbor; Department of Cancer Biology (M.K.), RIKEN Center for Integrative Medical Sciences (M.K., C.T.), Yokohama, Japan; Department of Medicine (L.L.), University of Colorado Denver, Anschutz Medical Campus, Aurora, CO; Department of Neurosciences, Experimental Neurology (R.L.), VIB Center, For Brain & Disease Research, KU Leuven-University of Leuven; Department of Neurology (R.L.), University Hospitals Leuven, Belgium; John Hunter Hospital (C.R.L.), Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia and Priority Research Centre for Stroke & Brain Injury, University of Newcastle, NSW, Australia; Peking University Health Science Center (L.L.), Department of Epidemiology and Biostatistics, Peking University, Beijing, China; Department of Neurology (S.L., J.F.M., O.A.R.), Mayo Clinic, Jacksonville, FL; Faculty of Health (J.M.), School of Nursing and Midwifery, University of Technology Sydney, NSW, Australia; Department of Neurology (T.M.), Helsinki University Central Hospital, Helsinki, Finland; Institute of Genetic Epidemiology (M.M.-N.), Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg; Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University Mainz, Germany; Department of Medicine I, Ludwig-Maximilians University Munich, Germany; Department of Medicine (C.C.H.) University of Maryland School of Medicine, Baltimore, MD; Health Research Board Clinical Research Facility (M.O.D.), Geata an Eolais, National University of Ireland, Galway; Department of Neurology (J.P., A.S.), Jagiellonian University, Krakow, Poland; Institute for Medical Information Sciences (A.P.), Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany; Department of Epidemiology (D.R.), Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; Psychiatric Genetics Unit (M.R., C.S.-M.), Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona; Department of Psychiatry (C.S.-M.), Hospital Universitari Vall d'Hebron, Barcelona; Biomedical Network Research Centre on Mental Health (CIBERSAM) (M.R.), Instituto de Salud Carlos III, Madrid; Department of Genetics (M.R.), Microbiology, and Statistics, Faculty of Biology, Universitat de Barcelona, Spain; McCance Center for Brain Health (J.R., C.D.A.), Massachusetts General Hospital; Center for Genomic Medicine (J.R.), MGH; Department of Neurology (J.R.), MGH, Boston; Program in Medical and Population Genetics (J.R.), Broad Institute, Cambridge, MA; Department of Neurology and Evelin F. McKnight Brain Institute (T.R., R.L.S.), Miller School of Medicine, University of Miami, FL; Institute of Cardiovascular Research (P.S.), Royal Holloway University of London, and Ashford and St. Peters Hospital (P.S.), Surrey, United Kingdom; Group Health Research Institute (N.L.S.), Group Health Cooperative; Department of Epidemiology (N.L.S.), University of Washington; Seattle Epidemiologic Research and Information Center (N.L.S.), VA Office of Research and Development, Seattle, WA; Department of Epidemiology and Population Health (S.W.-S.), Albert Einstein College of Medicine, New York; BHF Data Science Centre (C.L.S.), Health Data Research UK, London, United Kingdom; Department of Neurology (T.T.) and Department of Clinical Genetics and Genomics (C.J.), Region Vastra Gotaland, Sahlgrenska University Hospital; Department of Clinical Neuroscience (T.T.), Institute of Neurosciences and Physiology, Sahlgrenska Academy at University of Gothenburg, Sweden; Stroke Theme (V.T.), Florey Institute of Neuroscience and Mental Health, University of Melbourne; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Department of Neurology (J.H.V.), University Medical Center Utrecht Brain Center, Utrecht University, the Netherlands; Department of Neurology and Rehabilitation Medicine (D.W.), University of Cincinnati College of Medicine, OH; Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia School of Medicine, Charlottesville; Section of Neurology (A.G.L.), Skåne University Hospital, Lund, Sweden; Program in Medical and Population Genetics (C.D.A.), Broad Institute of MIT and Harvard, Cambridge, MA; Institute for Stroke and Dementia Research (ISD) (R.M., M.D.), University Hospital, LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (M.D.); German Center for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany; Geriatric Research and Education Clinical Center (B.D.M., S.J.K.), Veterans Administration Medical Center, Baltimore, MD. bmitchel@som.umaryland.edu.

PMID: 36240095
PMCID: PMC9620803
DOI: 10.1212/WNL.0000000000201006

Meta-Analysis

Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke

Thomas Jaworek et al. Neurology. 2022.

. 2022 Oct 17;99(16):e1738-e1754.

doi: 10.1212/WNL.0000000000201006.

Authors

Affiliations

¹ From the Division of Endocrinology (T.J., H.X., B.J.G, B.D.M., K.A.R., J.A.P., P.F.M.), Diabetes and Nutrition, Department of Neurology (J.W.C., N.S.F., H.L., S.J.K.), Division of Rheumatology and Clinical Immunology (M.C.H.), Department of Medicine, Department of Epidemiology and Public Health (M.C.H.), and Institute for Genome Sciences (T.D.O.C.), University of Maryland School of Medicine; VA Maryland Health Care System (J.W.C.); Centre for Medical Informatics (K.R., C.L.M.S.), Usher Institute, University of Edinburgh, United Kingdom; Institute of Biomedicine (T.M.S., C.J.), Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Neurology (L.T., J.P., D.S., T.T.), Helsinki University Hospital and University of Helsinki, Finland; Department of Molecular and Functional Genomics (V.A., J.L., R.Z.), Geisinger Health System, Danville, PA; LabEx DISTALZ-U1167 (P.A.), RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, University of Lille; Inserm U1167 (P.A.), Lille; Centre Hospitalier Universitaire Lille (P.A.); Institut Pasteur de Lille (P.A.), France; Department of Epidemiology (N.D.A., M.R.I.), University of Alabama at Birmingham; School of Medicine and Public Health (J.A., E.H.), University of Newcastle and Hunter Medical Research Institute, Australia; Stroke Research Group (S.B., H.S.M.), Department of Clinical Neurosciences, British Heart Foundation Cardiovascular Epidemiology Unit (A.B., J.D.), Department of Public Health and Primary Care, British Heart Foundation Centre of Research Excellence (A.B., J.D.), National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (A.B., J.D.), University of Cambridge (A.B., J.D.), United Kingdom; Department of Neurology (Q.R.B.), University of British Columbia, Vancouver, Canada; Department of Cerebrovascular Diseases (G.B.B.), Fondazione IRCCS Istituto Neurologico "Carlo Besta," Milan, Italy; Health Data Research UK Cambridge (A.B., J.D.); Wellcome Genome Campus (A.B., J.D.), Cambridge, United Kingdom; Stroke Pharmacogenomics and Genetics group (J.C.-M., I.F.-C., N.P.T.-A.), Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain; MRC Population Health Research Unit (Z.C., R.G.W.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Nuffield Department of Clinical Neurosciences (P.M.R.), University of Oxford, United Kingdom; DBCVS Research Institute (M.C., G.P.), Department of Pathology and Molecular Medicine, Population Health Research Institute, McMaster University; Thrombosis & Atherosclerosis Research Institute (TaARI) (M.C., G.P.), Hamilton, Ontario, Canada; Departments of Neurology (J.-M.L.) and Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; Department of Medicine and Laboratory for Clinical Biochemistry Research (J.P.D.), Department of Medicine, (M.C.), University of Vermont Larner College of Medicine, Burlington, VT; Department of Human Genetics (J.D.), Wellcome Sanger Institute, Hinxton, United Kingdom; University of Bordeaux (S.D., D.-A.T.), Inserm, Bordeux Population Health Research Center, UMR 1219; Department of Neurology (S.D.), Institute for Neurodegenerative Disease, Bordeaux University Hospital, France; Quantitative Medicine and Systems Biology Division (D.J.D.), Translational Genomics Research Institute, An Affiliate of City of Hope, Phoenix, AZ; Laboratory for Clinical Biochemistry Research (J.P.D.), Department of Clinical Sciences (G.E., J.A.S., M.S., D.R.W.), Malmö and Department of Clinical Sciences (A.I., M.S., A.G.L.), Neurology, Lund, Lund University, Sweden; Department of Neurology (C.E., R.S.), Medical University Graz, Austria; Survey Research Center (J.D.F.), Institute for Social Research, University of Michigan, Ann Arbor; Stroke Pharmacogenomics and Genetics (I.F.-C.), Fundacio Docència i Recerca MutuaTerrassa, Spain; Unit of Molecular Epidemiology (C.G.), Institute of Epidemiology (C.G., A.P.), Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg; Klinik und Poliklinik für Neurologie (A.-K.G.), Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Germany; Neuroscience Institute (R.P.G., L.R.P.), Saint Francis Medical Center, Trenton, NJ; Department for Biostatistics and Clinical Epidemiology (U.G., ), Charité-University Medical Centre, Berlin, Germany; National Institute for Health and Welfare (A.S.H., V.S.), Helsinki, Finland; Departments of Emergency Medicine and Neurology (L.H.), Washington University School of Medicine, St. Louis, MO; Division of Women's Health (K.R.), Department of Medicine and Department of Neurology (C.D.A.), Brigham and Women's Hospital, Harvard Medical School; Department of Epidemiology (J.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Neurology and Rehabilitation Medicine (A.I.), Skane University Hospital, Lund, Sweden; Division of Endocrinology (R.D.J.), Diabetes and Metabolism, Department of Internal Medicine and the Center for Clinical and Translational Science, The Ohio State University, Columbus; Department of Neurology (M.A.J., A.M.T., F.E.d.L.), Radboud University Medical Center, Donders Medical Center for Neuroscience, Nijmegen, the Netherlands; Department of Genetics, Microbiology and Statistics (R.R.J.), Institute of Biomedicine (IBUB), University of Barcelona; Institut de Recerca Sant Joan de Déu (R.R.J.), Esplugues de Llobregat; Centro de investigación biomédica en red (CIBERER) (R.R.J.); Neurovascular Research Group (NEUVAS) (J.J.-C.), Neurology Department, Institut Hospital del Mar d'Investigacio Medica, Universitat Autonoma de Barcelona, Spain; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (J.A.J., C.W.M.), University of Florida, College of Pharmacy; Division of Cardiovascular Medicine (J.A.J.), College of Medicine, University of Florida, Gainesville; Laboratory of Complex Trait Genomics (Y.K.), Graduate School of Frontier Sciences and Department of Cancer Biology (M.K.), Institute of Medical Science, The University of Tokyo, Japan; Department of Epidemiology (S.L.R.K.), School of Public Health, University of Michigan, Ann Arbor; Department of Cancer Biology (M.K.), RIKEN Center for Integrative Medical Sciences (M.K., C.T.), Yokohama, Japan; Department of Medicine (L.L.), University of Colorado Denver, Anschutz Medical Campus, Aurora, CO; Department of Neurosciences, Experimental Neurology (R.L.), VIB Center, For Brain & Disease Research, KU Leuven-University of Leuven; Department of Neurology (R.L.), University Hospitals Leuven, Belgium; John Hunter Hospital (C.R.L.), Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia and Priority Research Centre for Stroke & Brain Injury, University of Newcastle, NSW, Australia; Peking University Health Science Center (L.L.), Department of Epidemiology and Biostatistics, Peking University, Beijing, China; Department of Neurology (S.L., J.F.M., O.A.R.), Mayo Clinic, Jacksonville, FL; Faculty of Health (J.M.), School of Nursing and Midwifery, University of Technology Sydney, NSW, Australia; Department of Neurology (T.M.), Helsinki University Central Hospital, Helsinki, Finland; Institute of Genetic Epidemiology (M.M.-N.), Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg; Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University Mainz, Germany; Department of Medicine I, Ludwig-Maximilians University Munich, Germany; Department of Medicine (C.C.H.) University of Maryland School of Medicine, Baltimore, MD; Health Research Board Clinical Research Facility (M.O.D.), Geata an Eolais, National University of Ireland, Galway; Department of Neurology (J.P., A.S.), Jagiellonian University, Krakow, Poland; Institute for Medical Information Sciences (A.P.), Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany; Department of Epidemiology (D.R.), Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; Psychiatric Genetics Unit (M.R., C.S.-M.), Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona; Department of Psychiatry (C.S.-M.), Hospital Universitari Vall d'Hebron, Barcelona; Biomedical Network Research Centre on Mental Health (CIBERSAM) (M.R.), Instituto de Salud Carlos III, Madrid; Department of Genetics (M.R.), Microbiology, and Statistics, Faculty of Biology, Universitat de Barcelona, Spain; McCance Center for Brain Health (J.R., C.D.A.), Massachusetts General Hospital; Center for Genomic Medicine (J.R.), MGH; Department of Neurology (J.R.), MGH, Boston; Program in Medical and Population Genetics (J.R.), Broad Institute, Cambridge, MA; Department of Neurology and Evelin F. McKnight Brain Institute (T.R., R.L.S.), Miller School of Medicine, University of Miami, FL; Institute of Cardiovascular Research (P.S.), Royal Holloway University of London, and Ashford and St. Peters Hospital (P.S.), Surrey, United Kingdom; Group Health Research Institute (N.L.S.), Group Health Cooperative; Department of Epidemiology (N.L.S.), University of Washington; Seattle Epidemiologic Research and Information Center (N.L.S.), VA Office of Research and Development, Seattle, WA; Department of Epidemiology and Population Health (S.W.-S.), Albert Einstein College of Medicine, New York; BHF Data Science Centre (C.L.S.), Health Data Research UK, London, United Kingdom; Department of Neurology (T.T.) and Department of Clinical Genetics and Genomics (C.J.), Region Vastra Gotaland, Sahlgrenska University Hospital; Department of Clinical Neuroscience (T.T.), Institute of Neurosciences and Physiology, Sahlgrenska Academy at University of Gothenburg, Sweden; Stroke Theme (V.T.), Florey Institute of Neuroscience and Mental Health, University of Melbourne; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Department of Neurology (J.H.V.), University Medical Center Utrecht Brain Center, Utrecht University, the Netherlands; Department of Neurology and Rehabilitation Medicine (D.W.), University of Cincinnati College of Medicine, OH; Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia School of Medicine, Charlottesville; Section of Neurology (A.G.L.), Skåne University Hospital, Lund, Sweden; Program in Medical and Population Genetics (C.D.A.), Broad Institute of MIT and Harvard, Cambridge, MA; Institute for Stroke and Dementia Research (ISD) (R.M., M.D.), University Hospital, LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (M.D.); German Center for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany; Geriatric Research and Education Clinical Center (B.D.M., S.J.K.), Veterans Administration Medical Center, Baltimore, MD.
² From the Division of Endocrinology (T.J., H.X., B.J.G, B.D.M., K.A.R., J.A.P., P.F.M.), Diabetes and Nutrition, Department of Neurology (J.W.C., N.S.F., H.L., S.J.K.), Division of Rheumatology and Clinical Immunology (M.C.H.), Department of Medicine, Department of Epidemiology and Public Health (M.C.H.), and Institute for Genome Sciences (T.D.O.C.), University of Maryland School of Medicine; VA Maryland Health Care System (J.W.C.); Centre for Medical Informatics (K.R., C.L.M.S.), Usher Institute, University of Edinburgh, United Kingdom; Institute of Biomedicine (T.M.S., C.J.), Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Neurology (L.T., J.P., D.S., T.T.), Helsinki University Hospital and University of Helsinki, Finland; Department of Molecular and Functional Genomics (V.A., J.L., R.Z.), Geisinger Health System, Danville, PA; LabEx DISTALZ-U1167 (P.A.), RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, University of Lille; Inserm U1167 (P.A.), Lille; Centre Hospitalier Universitaire Lille (P.A.); Institut Pasteur de Lille (P.A.), France; Department of Epidemiology (N.D.A., M.R.I.), University of Alabama at Birmingham; School of Medicine and Public Health (J.A., E.H.), University of Newcastle and Hunter Medical Research Institute, Australia; Stroke Research Group (S.B., H.S.M.), Department of Clinical Neurosciences, British Heart Foundation Cardiovascular Epidemiology Unit (A.B., J.D.), Department of Public Health and Primary Care, British Heart Foundation Centre of Research Excellence (A.B., J.D.), National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (A.B., J.D.), University of Cambridge (A.B., J.D.), United Kingdom; Department of Neurology (Q.R.B.), University of British Columbia, Vancouver, Canada; Department of Cerebrovascular Diseases (G.B.B.), Fondazione IRCCS Istituto Neurologico "Carlo Besta," Milan, Italy; Health Data Research UK Cambridge (A.B., J.D.); Wellcome Genome Campus (A.B., J.D.), Cambridge, United Kingdom; Stroke Pharmacogenomics and Genetics group (J.C.-M., I.F.-C., N.P.T.-A.), Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain; MRC Population Health Research Unit (Z.C., R.G.W.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Nuffield Department of Clinical Neurosciences (P.M.R.), University of Oxford, United Kingdom; DBCVS Research Institute (M.C., G.P.), Department of Pathology and Molecular Medicine, Population Health Research Institute, McMaster University; Thrombosis & Atherosclerosis Research Institute (TaARI) (M.C., G.P.), Hamilton, Ontario, Canada; Departments of Neurology (J.-M.L.) and Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; Department of Medicine and Laboratory for Clinical Biochemistry Research (J.P.D.), Department of Medicine, (M.C.), University of Vermont Larner College of Medicine, Burlington, VT; Department of Human Genetics (J.D.), Wellcome Sanger Institute, Hinxton, United Kingdom; University of Bordeaux (S.D., D.-A.T.), Inserm, Bordeux Population Health Research Center, UMR 1219; Department of Neurology (S.D.), Institute for Neurodegenerative Disease, Bordeaux University Hospital, France; Quantitative Medicine and Systems Biology Division (D.J.D.), Translational Genomics Research Institute, An Affiliate of City of Hope, Phoenix, AZ; Laboratory for Clinical Biochemistry Research (J.P.D.), Department of Clinical Sciences (G.E., J.A.S., M.S., D.R.W.), Malmö and Department of Clinical Sciences (A.I., M.S., A.G.L.), Neurology, Lund, Lund University, Sweden; Department of Neurology (C.E., R.S.), Medical University Graz, Austria; Survey Research Center (J.D.F.), Institute for Social Research, University of Michigan, Ann Arbor; Stroke Pharmacogenomics and Genetics (I.F.-C.), Fundacio Docència i Recerca MutuaTerrassa, Spain; Unit of Molecular Epidemiology (C.G.), Institute of Epidemiology (C.G., A.P.), Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg; Klinik und Poliklinik für Neurologie (A.-K.G.), Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Germany; Neuroscience Institute (R.P.G., L.R.P.), Saint Francis Medical Center, Trenton, NJ; Department for Biostatistics and Clinical Epidemiology (U.G., ), Charité-University Medical Centre, Berlin, Germany; National Institute for Health and Welfare (A.S.H., V.S.), Helsinki, Finland; Departments of Emergency Medicine and Neurology (L.H.), Washington University School of Medicine, St. Louis, MO; Division of Women's Health (K.R.), Department of Medicine and Department of Neurology (C.D.A.), Brigham and Women's Hospital, Harvard Medical School; Department of Epidemiology (J.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Neurology and Rehabilitation Medicine (A.I.), Skane University Hospital, Lund, Sweden; Division of Endocrinology (R.D.J.), Diabetes and Metabolism, Department of Internal Medicine and the Center for Clinical and Translational Science, The Ohio State University, Columbus; Department of Neurology (M.A.J., A.M.T., F.E.d.L.), Radboud University Medical Center, Donders Medical Center for Neuroscience, Nijmegen, the Netherlands; Department of Genetics, Microbiology and Statistics (R.R.J.), Institute of Biomedicine (IBUB), University of Barcelona; Institut de Recerca Sant Joan de Déu (R.R.J.), Esplugues de Llobregat; Centro de investigación biomédica en red (CIBERER) (R.R.J.); Neurovascular Research Group (NEUVAS) (J.J.-C.), Neurology Department, Institut Hospital del Mar d'Investigacio Medica, Universitat Autonoma de Barcelona, Spain; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (J.A.J., C.W.M.), University of Florida, College of Pharmacy; Division of Cardiovascular Medicine (J.A.J.), College of Medicine, University of Florida, Gainesville; Laboratory of Complex Trait Genomics (Y.K.), Graduate School of Frontier Sciences and Department of Cancer Biology (M.K.), Institute of Medical Science, The University of Tokyo, Japan; Department of Epidemiology (S.L.R.K.), School of Public Health, University of Michigan, Ann Arbor; Department of Cancer Biology (M.K.), RIKEN Center for Integrative Medical Sciences (M.K., C.T.), Yokohama, Japan; Department of Medicine (L.L.), University of Colorado Denver, Anschutz Medical Campus, Aurora, CO; Department of Neurosciences, Experimental Neurology (R.L.), VIB Center, For Brain & Disease Research, KU Leuven-University of Leuven; Department of Neurology (R.L.), University Hospitals Leuven, Belgium; John Hunter Hospital (C.R.L.), Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia and Priority Research Centre for Stroke & Brain Injury, University of Newcastle, NSW, Australia; Peking University Health Science Center (L.L.), Department of Epidemiology and Biostatistics, Peking University, Beijing, China; Department of Neurology (S.L., J.F.M., O.A.R.), Mayo Clinic, Jacksonville, FL; Faculty of Health (J.M.), School of Nursing and Midwifery, University of Technology Sydney, NSW, Australia; Department of Neurology (T.M.), Helsinki University Central Hospital, Helsinki, Finland; Institute of Genetic Epidemiology (M.M.-N.), Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg; Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University Mainz, Germany; Department of Medicine I, Ludwig-Maximilians University Munich, Germany; Department of Medicine (C.C.H.) University of Maryland School of Medicine, Baltimore, MD; Health Research Board Clinical Research Facility (M.O.D.), Geata an Eolais, National University of Ireland, Galway; Department of Neurology (J.P., A.S.), Jagiellonian University, Krakow, Poland; Institute for Medical Information Sciences (A.P.), Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany; Department of Epidemiology (D.R.), Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; Psychiatric Genetics Unit (M.R., C.S.-M.), Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona; Department of Psychiatry (C.S.-M.), Hospital Universitari Vall d'Hebron, Barcelona; Biomedical Network Research Centre on Mental Health (CIBERSAM) (M.R.), Instituto de Salud Carlos III, Madrid; Department of Genetics (M.R.), Microbiology, and Statistics, Faculty of Biology, Universitat de Barcelona, Spain; McCance Center for Brain Health (J.R., C.D.A.), Massachusetts General Hospital; Center for Genomic Medicine (J.R.), MGH; Department of Neurology (J.R.), MGH, Boston; Program in Medical and Population Genetics (J.R.), Broad Institute, Cambridge, MA; Department of Neurology and Evelin F. McKnight Brain Institute (T.R., R.L.S.), Miller School of Medicine, University of Miami, FL; Institute of Cardiovascular Research (P.S.), Royal Holloway University of London, and Ashford and St. Peters Hospital (P.S.), Surrey, United Kingdom; Group Health Research Institute (N.L.S.), Group Health Cooperative; Department of Epidemiology (N.L.S.), University of Washington; Seattle Epidemiologic Research and Information Center (N.L.S.), VA Office of Research and Development, Seattle, WA; Department of Epidemiology and Population Health (S.W.-S.), Albert Einstein College of Medicine, New York; BHF Data Science Centre (C.L.S.), Health Data Research UK, London, United Kingdom; Department of Neurology (T.T.) and Department of Clinical Genetics and Genomics (C.J.), Region Vastra Gotaland, Sahlgrenska University Hospital; Department of Clinical Neuroscience (T.T.), Institute of Neurosciences and Physiology, Sahlgrenska Academy at University of Gothenburg, Sweden; Stroke Theme (V.T.), Florey Institute of Neuroscience and Mental Health, University of Melbourne; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Department of Neurology (J.H.V.), University Medical Center Utrecht Brain Center, Utrecht University, the Netherlands; Department of Neurology and Rehabilitation Medicine (D.W.), University of Cincinnati College of Medicine, OH; Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia School of Medicine, Charlottesville; Section of Neurology (A.G.L.), Skåne University Hospital, Lund, Sweden; Program in Medical and Population Genetics (C.D.A.), Broad Institute of MIT and Harvard, Cambridge, MA; Institute for Stroke and Dementia Research (ISD) (R.M., M.D.), University Hospital, LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (M.D.); German Center for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany; Geriatric Research and Education Clinical Center (B.D.M., S.J.K.), Veterans Administration Medical Center, Baltimore, MD. bmitchel@som.umaryland.edu.

PMID: 36240095
PMCID: PMC9620803
DOI: 10.1212/WNL.0000000000201006

Abstract

Background and objectives: Current genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke.

Methods: We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18-59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS.

Results: We observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008).

Discussion: The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.

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Figures

**Figure 1. Overview of the Study Design**

**Figure 2. Genome-wide Association Analysis of EOS**
Manhattan plot of EOS meta-analysis in the EOSC, random effects model, in TRANS ancestry (A) and European Ancestry (B). EOS = early-onset stroke; EOSC = Early Onset Stroke Consortium.

**Figure 3. Associations of SNPs at the *ABO* Locus With Multiple Traits**
Association plots showing SNPs associated with EOS at the *ABO* locus (±50 kb) and the corresponding associations of these SNPs with LOS (A), VTE (B), plasma levels of VWF (C), and plasma levels of factor VIII (D). EOS = early-onset stroke; LOS = late-onset stroke; SNP = single-nucleotide polymorphism; VWF = von Willebrand factor.

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References

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[1] Malik R, Chauhan G, Traylor M, et al. , AFGen Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology CHARGE Consortium, International Genomics of Blood Pressure iGEN-BP Consortium, INVENT Consortium, STARNET, BioBank Japan Cooperative Hospital Group, COMPASS Consortium, EPIC-CVD Consortium, EPIC-InterAct Consortium, International Stroke Genetics Consortium ISGC, METASTROKE Consortium, Neurology Working Group of the CHARGE Consortium, NINDS Stroke Genetics Network SiGN, UK Young Lacunar DNA Study, MEGASTROKE Consortium. Multiancestry genome-wide association study of 520, 000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018;50(4):524-537. - PMC - PubMed

[2] Malik R, Chauhan G, Traylor M, et al. , AFGen Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology CHARGE Consortium, International Genomics of Blood Pressure iGEN-BP Consortium, INVENT Consortium, STARNET, BioBank Japan Cooperative Hospital Group, COMPASS Consortium, EPIC-CVD Consortium, EPIC-InterAct Consortium, International Stroke Genetics Consortium ISGC, METASTROKE Consortium, Neurology Working Group of the CHARGE Consortium, NINDS Stroke Genetics Network SiGN, UK Young Lacunar DNA Study, MEGASTROKE Consortium. Multiancestry genome-wide association study of 520, 000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018;50(4):524-537. - PMC - PubMed

[3] Malik R, Rannikmae K, Traylor M, et al. , MEGASTROKE consortium and the International Stroke Genetics Consortium. Genome-wide meta-analysis identifies 3 novel loci associated with stroke. Ann Neurol. 2018;84(6):934-939. - PMC - PubMed

[4] Malik R, Rannikmae K, Traylor M, et al. , MEGASTROKE consortium and the International Stroke Genetics Consortium. Genome-wide meta-analysis identifies 3 novel loci associated with stroke. Ann Neurol. 2018;84(6):934-939. - PMC - PubMed

[5] MacClellan LR, Mitchell BD, Cole JW, et al. . Familial aggregation of ischemic stroke in young women: the Stroke Prevention in Young Women Study. Genet Epidemiol. 2006;30(7):602-608. - PubMed

[6] MacClellan LR, Mitchell BD, Cole JW, et al. . Familial aggregation of ischemic stroke in young women: the Stroke Prevention in Young Women Study. Genet Epidemiol. 2006;30(7):602-608. - PubMed

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Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke

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Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke

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