Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

• Type of Material: Article
• Authors: Rainer Malik, University Hospital; Ganesh Chauhan, Indian Institute of Science; Matthew Traylor, University of Cambridge; Muralidharan Sargurupremraj, Bordeaux University Hospital; Yukinori Okada, Immunology Frontier Research Center; Aniket Mishra, Bordeaux University Hospital; Loes Rutten-Jacobs, University of Cambridge; Anne-Katrin Giese, Harvard Medical School; Sander W. van der Laan, University Medical Center Utrecht; Solveig Gretarsdottir, DeCODE Genet AMGEN Inc; Christopher D. Anderson, MGH; Michael Chong, McMaster University; Hieab H. H. Adams, Erasmus University Medical Center; Tetsuro Ago, Kyushu University; Peter Almgren, Lund University; Philippe Amouyel, Université Lille; Hakan Ay, MGH; Traci M Bartz, University of Washington; Oscar R. Benavente, University of British Columbia; Steve Bevan, University of Lincoln; Giorgio B. Boncoraglio, IRCCS; Robert D. Brown, Mayo Clinic; Adam S. Butterworth, University of Cambridge; Caty Carrera, Neurology and Medicine Departments-Universitat Autònoma de Barcelona; Cara L. Carty, Children’s National Medical Center; Daniel I. Chasman, Brigham and Women’s Hospital; Wei-Min Chen, University of Virginia; John W. Cole, University of Maryland; Adolfo Correa, University of Mississippi; Ioana Cotlarciuc, Royal Holloway University of London; Carlos Cruchaga, Washington University School of Medicine; John Danesh, University of Cambridge; Paul I. W. de Bakker, University Medical Center Utrecht; Anita L. DeStefano, Boston University; Marcel den Hoed, Uppsala University; Qing Duan, University of North Carolina; Stefan T. Engelter, Basel University Hospital; Guido J. Falcone, Yale University; Rebecca F. Gottesman, Johns Hopkins University; Raji P. Grewal, SF Medical Center; Vilmunder Gudnason, Icelandic Heart Association Research Institute; Stefan Gustafsson, Johns Hopkins University; Jeffery Haessler, SF Medical Center; Tamara B Harris, National Institute of Health; Ahamad Hassan, Leeds Teaching Hospitals NHS Trust; Aki S. Havulinna, National Institute for Health and Welfare; Susan R. Heckbert, University of Washington; Elizabeth G. Holliday, Hunter Medical Research Institute; George Howard, University of Alabama Birmingham; Fang-Chi Hsu, Wake Forest School of Medicine; Hyacinth Hyacinth, Emory University; M. Arfan Ikram, Erasmus University Medical Center; Erik Ingelsson, Stanford University; Marguerite R. Irvin, University of Alabama Birmingham; Xuequi Jian, University of Texas Health Science Center at Houston; Jordi Jimenez-Conde, Universitat Autònoma de Barcelona; Julie A. Johnson, University of Florida; J. Wouter Jukema, Leiden University; Masahiro Kanai, University of Newcastle; Keith L. Keene, East Carolina University; Brett M. Kissela, University of Cincinnati; Dawn O. Kleindorfer, University of Cincinnati; Charles Kooperberg, Fred Hutchinson Cancer Research Center; Michiaki Kubo, University of Newcastle; Leslie A. Lange, University of Colorado Denver; Carl D. Langefeld, Wake Forest School of Medicine; Claudia Langenberg, University of Cambridge; Lenore J. Launer, NIH; Jin-Moo Lee, Washington University School of Medicine; Robin Lemmens, KU Leuven-University of Leuven; Didier Leys, Universite Lille; Cathryn M. Lewis, Kings College London; Wei-Yun Lin, University of Cambridge; Arne G. Lindgren, Lund University; Erik Lorentzen, University of Gothenburg; Patrik K. Magnusson, Karolinska Institutet; Jane Maguire, University of Technology Sydney; Ani Manichaikul, University of Virginia; Patrick F. McArdle, University of Maryland; James F. Meschia, Mayo Clinic; Braxton D. Mitchell, University of Maryland; Thomas H. Mosley, University of Mississippi
• Language: English
• Date: 2018-04-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 The Author(s).
• Final Published Version (URL): http://dx.doi.org/10.1038/s41588-018-0058-3
• Title of Journal or Parent Work: Nature Genetics
• ISSN: 1061-4036
• Volume: 50
• Issue: 4
• Start Page: 524
• End Page: +
• Grant/Funding Information: P.T.E. is the PI on a grant from Bayer HealthCare to the Broad Institute, focused on the genetics and therapeutics of atrial fibrillation.
• Keywords: ATRIAL-FIBRILLATION; COMPLEX TRAITS; SUDDEN CARDIAC DEATH; Science & Technology; SUSCEPTIBILITY LOCI; HEMORRHAGIC STROKE; HUMAN GENETIC-VARIATION; ISCHEMIC-STROKE; WHITE-MATTER HYPERINTENSITIES; Life Sciences & Biomedicine; SMALL-VESSEL DISEASE; Genetics & Heredity; CORONARY-ARTERY-DISEASE
• Research Categories: Biology, Genetics; Health Sciences, Medicine and Surgery

Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.