Nat Genet. 2018 Apr;50(4):524-537. doi: 10.1038/s41588-018-0058-3. Epub 2018 Mar 12.

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

Malik R¹, Chauhan G², Traylor M³, Sargurupremraj M^4,⁵, Okada Y^6,^7,⁸, Mishra A^4,⁵, Rutten-Jacobs L³, Giese AK⁹, van der Laan SW¹⁰, Gretarsdottir S¹¹, Anderson CD^12,^13,¹⁴, Chong M¹⁵, Adams HHH^16,¹⁷, Ago T¹⁸, Almgren P¹⁹, Amouyel P^20,²¹, Ay H^13,²², Bartz TM²³, Benavente OR²⁴, Bevan S²⁵, Boncoraglio GB²⁶, Brown RD Jr²⁷, Butterworth AS^28,²⁹, Carrera C^30,³¹, Carty CL^32,³³, Chasman DI^34,³⁵, Chen WM³⁶, Cole JW³⁷, Correa A³⁸, Cotlarciuc I³⁹, Cruchaga C^40,⁴¹, Danesh J^28,^42,^43,⁴⁴, de Bakker PIW^45,⁴⁶, DeStefano AL^47,⁴⁸, den Hoed M⁴⁹, Duan Q⁵⁰, Engelter ST^51,⁵², Falcone GJ^53,⁵⁴, Gottesman RF⁵⁵, Grewal RP⁵⁶, Gudnason V^57,⁵⁸, Gustafsson S⁵⁹, Haessler J⁶⁰, Harris TB⁶¹, Hassan A⁶², Havulinna AS^63,⁶⁴, Heckbert SR⁶⁵, Holliday EG^66,⁶⁷, Howard G⁶⁸, Hsu FC⁶⁹, Hyacinth HI⁷⁰, Ikram MA¹⁶, Ingelsson E^71,⁵⁹, Irvin MR⁷², Jian X⁷³, Jiménez-Conde J⁷⁴, Johnson JA^75,⁷⁶, Jukema JW⁷⁷, Kanai M^6,^7,⁷⁸, Keene KL^79,⁸⁰, Kissela BM⁸¹, Kleindorfer DO⁸¹, Kooperberg C⁶⁰, Kubo M⁸², Lange LA⁸³, Langefeld CD⁸⁴, Langenberg C⁸⁵, Launer LJ⁸⁶, Lee JM⁸⁷, Lemmens R^88,⁸⁹, Leys D⁹⁰, Lewis CM^91,⁹², Lin WY^28,⁹³, Lindgren AG^94,⁹⁵, Lorentzen E⁹⁶, Magnusson PK⁹⁷, Maguire J⁹⁸, Manichaikul A³⁶, McArdle PF⁹⁹, Meschia JF¹⁰⁰, Mitchell BD^99,¹⁰¹, Mosley TH^102,¹⁰³, Nalls MA^104,¹⁰⁵, Ninomiya T¹⁰⁶, O'Donnell MJ^15,¹⁰⁷, Psaty BM^108,^65,^109,¹¹⁰, Pulit SL^45,¹¹¹, Rannikmäe K^112,¹¹³, Reiner AP^65,¹¹⁴, Rexrode KM¹¹⁵, Rice K¹¹⁶, Rich SS³⁶, Ridker PM^34,³⁵, Rost NS^9,¹³, Rothwell PM¹¹⁷, Rotter JI^118,¹¹⁹, Rundek T¹²⁰, Sacco RL¹²⁰, Sakaue S^7,¹²¹, Sale MM¹²², Salomaa V⁶³, Sapkota BR¹²³, Schmidt R¹²⁴, Schmidt CO¹²⁵, Schminke U¹²⁶, Sharma P³⁹, Slowik A¹²⁷, Sudlow CLM^112,¹¹³, Tanislav C¹²⁸, Tatlisumak T^129,¹³⁰, Taylor KD^118,¹¹⁹, Thijs VNS^131,¹³², Thorleifsson G¹¹, Thorsteinsdottir U¹¹, Tiedt S¹, Trompet S¹³³, Tzourio C^5,^134,¹³⁵, van Duijn CM^136,¹³⁷, Walters M¹³⁸, Wareham NJ⁸⁵, Wassertheil-Smoller S¹³⁹, Wilson JG¹⁴⁰, Wiggins KL¹⁰⁸, Yang Q⁴⁷, Yusuf S¹⁵, Bis JC¹⁰⁸, Pastinen T¹⁴¹, Ruusalepp A^142,^143,¹⁴⁴, Schadt EE¹⁴⁵, Koplev S¹⁴⁵, Björkegren JLM^145,^146,^147,¹⁴⁴, Codoni V^148,¹⁴⁹, Civelek M^122,¹⁵⁰, Smith NL^65,^151,¹⁵², Trégouët DA^148,¹⁴⁹, Christophersen IE^54,^153,¹⁵⁴, Roselli C⁵⁴, Lubitz SA^54,¹⁵³, Ellinor PT^54,¹⁵³, Tai ES¹⁵⁵, Kooner JS¹⁵⁶, Kato N¹⁵⁷, He J¹⁵⁸, van der Harst P¹⁵⁹, Elliott P¹⁶⁰, Chambers JC^161,¹⁶², Takeuchi F¹⁵⁷, Johnson AD^48,¹⁶³, Sanghera DK^123,^164,¹⁶⁵, Melander O¹⁹, Jern C¹⁶⁶, Strbian D^167,¹⁶⁸, Fernandez-Cadenas I^30,³¹, Longstreth WT Jr^65,¹⁶⁹, Rolfs A¹⁷⁰, Hata J¹⁰⁶, Woo D⁸¹, Rosand J^12,^13,¹⁴, Pare G¹⁵, Hopewell JC¹⁷¹, Saleheen D¹⁷², Stefansson K^11,⁵⁸, Worrall BB¹⁷³, Kittner SJ³⁷, Seshadri S^48,¹⁷⁴, Fornage M^73,¹⁷⁵, Markus HS³, Howson JMM²⁸, Kamatani Y^6,¹⁷⁶, Debette S^177,¹⁷⁸, Dichgans M^179,^180,¹⁸¹, Malik R¹, Chauhan G², Traylor M³, Sargurupremraj M^4,⁵, Okada Y^6,^7,⁸, Mishra A^4,⁵, Rutten-Jacobs L³, Giese AK⁹, van der Laan SW¹⁰, Gretarsdottir S¹¹, Anderson CD^12,^13,¹⁴, Chong M¹⁵, Adams HHH^16,¹⁷, Ago T¹⁸, Almgren P¹⁹, Amouyel P^20,²¹, Ay H^13,²², Bartz TM²³, Benavente OR²⁴, Bevan S²⁵, Boncoraglio GB²⁶, Brown RD Jr²⁷, Butterworth AS^28,²⁹, Carrera C^30,³¹, Carty CL^32,³³, Chasman DI^34,³⁵, Chen WM³⁶, Cole JW³⁷, Correa A³⁸, Cotlarciuc I³⁹, Cruchaga C^40,⁴¹, Danesh J^28,^42,^43,⁴⁴, de Bakker PIW^45,⁴⁶, DeStefano AL^47,⁴⁸, Hoed MD⁴⁹, Duan Q⁵⁰, Engelter ST^51,⁵², Falcone GJ^53,⁵⁴, Gottesman RF⁵⁵, Grewal RP⁵⁶, Gudnason V^57,⁵⁸, Gustafsson S⁵⁹, Haessler J⁶⁰, Harris TB⁶¹, Hassan A⁶², Havulinna AS^63,⁶⁴, Heckbert SR⁶⁵, Holliday EG^66,⁶⁷, Howard G⁶⁸, Hsu FC⁶⁹, Hyacinth HI⁷⁰, Ikram MA¹⁶, Ingelsson E^71,⁵⁹, Irvin MR⁷², Jian X⁷³, Jiménez-Conde J⁷⁴, Johnson JA^75,⁷⁶, Jukema JW⁷⁷, Kanai M^6,^7,⁷⁸, Keene KL^79,⁸⁰, Kissela BM⁸¹, Kleindorfer DO⁸¹, Kooperberg C⁶⁰, Kubo M⁸², Lange LA⁸³, Langefeld CD⁸⁴, Langenberg C⁸⁵, Launer LJ⁸⁶, Lee JM⁸⁷, Lemmens R^88,⁸⁹, Leys D⁹⁰, Lewis CM^91,⁹², Lin WY^28,⁹³, Lindgren AG^94,⁹⁵, Lorentzen E⁹⁶, Magnusson PK⁹⁷, Maguire J⁹⁸, Manichaikul A³⁶, McArdle PF⁹⁹, Meschia JF¹⁰⁰, Mitchell BD^99,¹⁰¹, Mosley TH^102,¹⁰³, Nalls MA^104,¹⁰⁵, Ninomiya T¹⁰⁶, O'Donnell MJ^15,¹⁰⁷, Psaty BM^108,^65,^109,¹¹⁰, Pulit SL^45,¹¹¹, Rannikmäe K^112,¹¹³, Reiner AP^65,¹¹⁴, Rexrode KM¹¹⁵, Rice K¹¹⁶, Rich SS³⁶, Ridker PM^34,³⁵, Rost NS^9,¹³, Rothwell PM¹¹⁷, Rotter JI^118,¹¹⁹, Rundek T¹²⁰, Sacco RL¹²⁰, Sakaue S^7,¹²¹, Sale MM¹²², Salomaa V⁶³, Sapkota BR¹²³, Schmidt R¹²⁴, Schmidt CO¹²⁵, Schminke U¹²⁶, Sharma P³⁹, Slowik A¹²⁷, Sudlow CLM^112,¹¹³, Tanislav C¹²⁸, Tatlisumak T^129,¹³⁰, Taylor KD^118,¹¹⁹, Thijs VNS^131,¹³², Thorleifsson G¹¹, Thorsteinsdottir U¹¹, Tiedt S¹, Trompet S¹³³, Tzourio C^5,^134,¹³⁵, van Duijn CM^136,¹³⁷, Walters M¹³⁸, Wareham NJ⁸⁵, Wassertheil-Smoller S¹³⁹, Wilson JG¹⁴⁰, Wiggins KL¹⁰⁸, Yang Q⁴⁷, Yusuf S¹⁵, Amin N¹⁶, Aparicio HS^48,¹⁸², Arnett DK¹⁸³, Attia J¹⁸⁴, Beiser AS^47,⁴⁸, Berr C¹⁸⁵, Buring JE^34,³⁵, Bustamante M¹⁸⁶, Caso V¹⁸⁷, Cheng YC⁹⁹, Choi SH^48,¹⁸⁸, Chowhan A^48,¹⁸², Cullell N³¹, Dartigues JF^189,¹⁹⁰, Delavaran H^94,⁹⁵, Delgado P¹⁹¹, Dörr M^192,¹⁹³, Engström G¹⁹, Ford I¹⁹⁴, Gurpreet WS¹⁹⁵, Hamsten A^196,¹⁹⁷, Heitsch L¹⁹⁸, Hozawa A¹⁹⁹, Ibanez L²⁰⁰, Ilinca A^94,⁹⁵, Ingelsson M²⁰¹, Iwasaki M²⁰², Jackson RD²⁰³, Jood K²⁰⁴, Jousilahti P⁶³, Kaffashian S^4,⁵, Kalra L²⁰⁵, Kamouchi M²⁰⁶, Kitazono T¹⁸, Kjartansson O²⁰⁷, Kloss M²⁰⁸, Koudstaal PJ²⁰⁹, Krupinski J²¹⁰, Labovitz DL²¹¹, Laurie CC¹¹⁶, Levi CR²¹², Li L²¹³, Lind L²¹⁴, Lindgren CM^215,²¹⁶, Lioutas V^48,²¹⁷, Liu YM²¹⁸, Lopez OL²¹⁹, Makoto H²²⁰, Martinez-Majander N¹⁶⁷, Matsuda K²²⁰, Minegishi N¹⁹⁹, Montaner J³⁰, Morris AP^221,²²², Muiño E³¹, Müller-Nurasyid M^223,^224,²²⁵, Norrving B^94,⁹⁵, Ogishima S¹⁹⁹, Parati EA²⁶, Peddareddygari LR⁵⁶, Pedersen NL^97,²²⁶, Pera J¹²⁷, Perola M^63,²²⁷, Pezzini A²²⁸, Pileggi S²²⁹, Rabionet R²³⁰, Riba-Llena I³⁰, Ribasés M²³¹, Romero JR^48,¹⁸², Roquer J^232,²³³, Rudd AG^234,²³⁵, Sarin AP^64,²³⁶, Sarju R¹⁹⁵, Sarnowski C^47,⁴⁸, Sasaki M²³⁷, Satizabal CL^48,¹⁸², Satoh M²³⁷, Sattar N²³⁸, Sawada N²⁰², Sibolt G¹⁶⁷, Sigurdsson Á²³⁹, Smith A²⁴⁰, Sobue K²³⁷, Soriano-Tárraga C²³³, Stanne T²⁴¹, Stine OC²⁴², Stott DJ²⁴³, Strauch K^223,²⁴⁴, Takai T¹⁹⁹, Tanaka H^245,²⁴⁶, Tanno K²³⁷, Teumer A¹²⁵, Tomppo L¹⁶⁷, Torres-Aguila NP³¹, Touze E^247,²⁴⁸, Tsugane S²⁰², Uitterlinden AG²⁴⁹, Valdimarsson EM²⁵⁰, van der Lee SJ¹⁶, Völzke H¹²⁵, Wakai K²⁴⁵, Weir D²⁵¹, Williams SR²⁵², Wolfe CDA^234,²³⁵, Wong Q¹¹⁶, Xu H⁹⁹, Yamaji T²⁰², Sanghera DK^123,^164,¹⁶⁵, Melander O¹⁹, Jern C¹⁶⁶, Strbian D^167,¹⁶⁸, Fernandez-Cadenas I^30,³¹, Longstreth WT Jr^65,¹⁶⁹, Rolfs A¹⁷⁰, Hata J¹⁰⁶, Woo D⁸¹, Rosand J^12,^13,¹⁴, Pare G¹⁵, Hopewell JC¹⁷¹, Saleheen D¹⁷², Stefansson K^11,⁵⁸, Worrall BB¹⁷³, Kittner SJ³⁷, Seshadri S^48,¹⁷⁴, Fornage M^73,¹⁷⁵, Markus HS³, Howson JMM²⁸, Kamatani Y^6,¹⁷⁶, Debette S^4,⁵, Dichgans M^1,^253,²⁵⁴; 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; MEGASTROKE Consortium:.

Author information

1: Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
2: Centre for Brain Research, Indian Institute of Science, Bangalore, India.
3: INSERM U1219 Bordeaux Population Health Research Center, University of Bordeaux, France.
4: Stroke Research Group, Division of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
5: Department of Neurology, Institute for Neurodegenerative Disease, Bordeaux University Hospital, Bordeaux, France.
6: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
7: Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
8: Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
9: Department of Neurology, Massachusetts General Hospital (MGH), Harvard Medical School, Boston, MA, USA.
10: Laboratory of Experimental Cardiology, Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands.
11: deCODE genetics/AMGEN Inc., Reykjavik, Iceland.
12: Center for Genomic Medicine, MGH, Boston, MA, USA.
13: J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA, USA.
14: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
15: Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
16: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
17: Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
18: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
19: Department of Clinical Sciences, Lund University, Malmö, Sweden.
20: INSERM, Institut Pasteur de Lille, LabEx DISTALZ-UMR1167, Risk Factors and Molecular Determinants of Aging-Related Diseases, Université Lille, Lille, France.
21: Centre Hospitalier Université Lille, Epidemiology and Public Health Department, Lille, France.
22: AA Martinos Center for Biomedical Imaging, Department of Radiology, MGH, Harvard Medical School, Boston, MA, USA.
23: Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, Seattle, WA, USA.
24: Division of Neurology, Faculty of Medicine, Brain Research Center, University of British Columbia, Vancouver, British Columbia, Canada.
25: School of Life Science, University of Lincoln, Lincoln, UK.
26: Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
27: Department of Neurology, Mayo Clinic Rochester, Rochester, MN, USA.
28: MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
29: National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
30: Neurovascular Research Laboratory, Vall d'Hebron Institut of Research, Neurology and Medicine Departments-Universitat Autònoma de Barcelona, Vall d'Hebrón Hospital, Barcelona, Spain.
31: Stroke Pharmacogenomics and Genetics, Fundacio Docència i Recerca MutuaTerrassa, Terrassa, Spain.
32: Children's Research Institute, Children's National Medical Center, Washington, DC, USA.
33: Center for Translational Science, George Washington University, Washington, DC, USA.
34: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
35: Harvard Medical School, Boston, MA, USA.
36: Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
37: Department of Neurology, University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA.
38: Departments of Medicine, Pediatrics and Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.
39: Institute of Cardiovascular Research, Royal Holloway University of London, London, UK, and Ashford and St Peters Hospital, Surrey, UK.
40: Department of Psychiatry, Hope Center Program on Protein Aggregation and Neurodegeneration (HPAN), Washington University School of Medicine, St. Louis, MO, USA.
41: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
42: NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
43: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
44: British Heart Foundation, Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, UK.
45: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
46: Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
47: Boston University School of Public Health, Boston, MA, USA.
48: Framingham Heart Study, Framingham, MA, USA.
49: Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
50: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
51: Department of Neurology and Stroke Center, Basel University Hospital, Basel, Switzerland.
52: Neurorehabilitation Unit, University of Basel and University Center for Medicine of Aging and Rehabilitation Basel, Felix Platter Hospital, Basel, Switzerland.
53: Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.
54: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
55: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
56: Neuroscience Institute, SF Medical Center, Trenton, NJ, USA.
57: Icelandic Heart Association Research Institute, Kopavogur, Iceland.
58: Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
59: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
60: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
61: Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
62: Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
63: National Institute for Health and Welfare, Helsinki, Finland.
64: FIMM-Institute for Molecular Medicine Finland, Helsinki, Finland.
65: Department of Epidemiology, University of Washington, Seattle, WA, USA.
66: Public Health Stream, Hunter Medical Research Institute, New Lambton, New South Wales, Australia.
67: Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia.
68: School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
69: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
70: Aflac Cancer and Blood Disorder Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
71: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
72: Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
73: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
74: Neurovascular Research Group (NEUVAS), Neurology Department, Institut Hospital del Mar d'Investigació Mèdica, Universitat Autònoma de Barcelona, Barcelona, Spain.
75: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, College of Pharmacy, Gainesville, FL, USA.
76: Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
77: Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
78: Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.
79: Department of Biology, East Carolina University, Greenville, NC, USA.
80: Center for Health Disparities, East Carolina University, Greenville, NC, USA.
81: University of Cincinnati College of Medicine, Cincinnati, OH, USA.
82: RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
83: Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
84: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
85: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.
86: Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
87: Department of Neurology, Radiology, and Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, USA.
88: Department of Neurosciences, Experimental Neurology, KU Leuven-University of Leuven, Leuven, Belgium.
89: VIB Center for Brain & Disease Research, University Hospitals Leuven, Department of Neurology, Leuven, Belgium.
90: INSERM U 1171, CHU Lille, Université Lille, Lille, France.
91: Department of Medical and Molecular Genetics, King's College London, London, UK.
92: SGDP Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
93: Northern Institute for Cancer Research, Newcastle University, Newcastle, UK.
94: Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden.
95: Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden.
96: Bioinformatics Core Facility, University of Gothenburg, Gothenburg, Sweden.
97: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
98: University of Technology Sydney, Faculty of Health, Ultimo, New South Wales, Australia.
99: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
100: Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
101: Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
102: Division of Geriatrics, School of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
103: Memory Impairment and Neurodegenerative Dementia Center, University of Mississippi Medical Center, Jackson, MS, USA.
104: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
105: Data Tecnica International, Glen Echo, MD, USA.
106: Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
107: Clinical Research Facility, Department of Medicine, NUI Galway, Galway, Ireland.
108: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
109: Department of Health Services, University of Washington, Seattle, WA, USA.
110: Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
111: Brain Center Rudolf Magnus, Department of Neurology, University Medical Center Utrecht, Utrecht, the Netherlands.
112: Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
113: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
114: Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
115: Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
116: Department of Biostatistics, University of Washington, Seattle, WA, USA.
117: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
118: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
119: Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
120: Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA.
121: Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
122: Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
123: Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
124: Department of Neurology, Medical University of Graz, Graz, Austria.
125: Institute for Community Medicine, SHIP-KEF, University Medicine Greifswald, Greifswald, Germany.
126: Department of Neurology, University Medicine Greifswald, Greifswald, Germany.
127: Department of Neurology, Jagiellonian University, Krakow, Poland.
128: Department of Neurology, Justus Liebig University, Giessen, Germany.
129: Department of Clinical Neurosciences/Neurology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
130: Sahlgrenska University Hospital, Gothenburg, Sweden.
131: Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Victoria, Australia.
132: Austin Health, Department of Neurology, Heidelberg, Victoria, Australia.
133: Department of Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
134: INSERM, U1219, Bordeaux, France.
135: Department of Public Health, Bordeaux University Hospital, Bordeaux, France.
136: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
137: Center for Medical Systems Biology, Leiden, the Netherlands.
138: School of Medicine, Dentistry and Nursing at the University of Glasgow, Glasgow, UK.
139: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA.
140: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
141: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
142: Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia.
143: Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia.
144: Clinical Gene Networks AB, Stockholm, Sweden.
145: Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, New York, NY, USA.
146: Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, Biomeedikum, University of Tartu, Tartu, Estonia.
147: Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden.
148: UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Sorbonne Universités, Paris, France.
149: ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
150: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
151: Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
152: Seattle Epidemiologic Research and Information Center, VA Office of Research and Development, Seattle, WA, USA.
153: Cardiovascular Research Center, MGH, Boston, MA, USA.
154: Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway.
155: Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
156: National Heart and Lung Institute, Imperial College London, London, UK.
157: Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
158: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
159: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
160: MRC-PHE Centre for Environment and Health, School of Public Health, Department of Epidemiology and Biostatistics and the NIHR Imperial Biomedical Research Centre, Imperial College London, London, UK.
161: Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
162: Department of Cardiology, Ealing Hospital NHS Trust, Southall, UK.
163: National Heart, Lung and Blood Research Institute, Division of Intramural Research, Population Sciences Branch, Framingham, MA, USA.
164: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
165: Oklahoma Center for Neuroscience, Oklahoma City, OK, USA.
166: Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
167: Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
168: Clinical Neurosciences, Neurology, University of Helsinki, Helsinki, Finland.
169: Department of Neurology, University of Washington, Seattle, WA, USA.
170: Albrecht Kossel Institute, University Clinic of Rostock, Rostock, Germany.
171: Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
172: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
173: Departments of Neurology and Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.
174: Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, San Antonio, TX, USA.
175: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
176: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
177: Stroke Research Group, Division of Clinical Neurosciences, University of Cambridge, Cambridge, UK. stephanie.debette@u-bordeaux.fr.
178: Department of Neurology, Institute for Neurodegenerative Disease, Bordeaux University Hospital, Bordeaux, France. stephanie.debette@u-bordeaux.fr.
179: Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany. martin.dichgans@med.uni-muenchen.de.
180: Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. martin.dichgans@med.uni-muenchen.de.
181: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. martin.dichgans@med.uni-muenchen.de.
182: Boston University School of Medicine, Boston, MA, USA.
183: University of Kentucky College of Public Health, Lexington, KY, USA.
184: University of Newcastle and Hunter Medical Research Institute, New Lambton, New South Wales, Australia.
185: INSERM, U1061, Université Montpellier, Montpellier, France.
186: Centre for Research in Environmental Epidemiology, Barcelona, Spain.
187: Department of Neurology, Università degli Studi di Perugia, Umbria, Italy.
188: Broad Institute, Cambridge, MA, USA.
189: Bordeaux Population Health Research Center, INSERM, UMR 1219, Université Bordeaux, Bordeaux, France.
190: Department of Neurology, Memory Clinic, Bordeaux University Hospital, Bordeaux, France.
191: Neurovascular Research Laboratory. Vall d'Hebron Institut of Research, Neurology and Medicine Departments-Universitat Autònoma de Barcelona. Vall d'Hebrón Hospital, Barcelona, Spain.
192: Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
193: DZHK, Greifswald, Germany.
194: Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
195: Hero DMC Heart Institute, Dayanand Medical College & Hospital, Ludhiana, India.
196: Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
197: Karolinska Institutet, Stockholm, Sweden.
198: Division of Emergency Medicine, and Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
199: Tohoku Medical Megabank Organization, Sendai, Japan.
200: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
201: Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden.
202: Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
203: Department of Internal Medicine and the Center for Clinical and Translational Science, Ohio State University, Columbus, OH, USA.
204: Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Goteborg, Sweden.
205: Department of Basic and Clinical Neurosciences, King's College London, London, UK.
206: Department of Health Care Administration and Management, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
207: Departments of Neurology & Radiology, Landspitali National University Hospital, Reykjavik, Iceland.
208: Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
209: Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands.
210: Hospital Universitari Mutua Terrassa, Terrassa (Barcelona), Spain.
211: Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY, USA.
212: John Hunter Hospital, Hunter Medical Research Institute and University of Newcastle, Newcastle, New South Wales, Australia.
213: Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
214: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
215: Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
216: Wellcome Trust Centre for Human Genetics, Oxford, UK.
217: Beth Israel Deaconess Medical Center, Boston, MA, USA.
218: Wake Forest School of Medicine, Wake Forest, NC, USA.
219: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
220: BioBank Japan, Laboratory of Clinical Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.
221: Department of Biostatistics, University of Liverpool, Liverpool, UK.
222: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
223: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
224: Department of Medicine I, Ludwig-Maximilians-Universität, Munich, Germany.
225: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
226: MEB, Karolinska Institutet, Stockholm, Sweden.
227: Estonian Genome Center, University of Tartu, Tartu, Estonia.
228: Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Brescia, Italy.
229: Translational Genomics Unit, Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
230: Department of Genetics, Microbiology and Statistics, University of Barcelona, Barcelona, Spain.
231: Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
232: Department of Neurology, IMIM-Hospital del Mar, and Universitat Autònoma de Barcelona, Barceloina, Spain.
233: IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
234: National Institute for Health Research Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust and King's College London, London, UK.
235: Division of Health and Social Care Research, King's College London, London, UK.
236: THL-National Institute for Health and Welfare, Helsinki, Finland.
237: Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.
238: BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, UK.
239: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
240: Icelandic Heart Association, Reykjavik, Iceland.
241: Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Goteborg, Sweden.
242: Department of Epidemiology, University of Maryland School of Medicine, Baltimore, MD, USA.
243: Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK.
244: IBE, Faculty of Medicine, LMU Munich, Munich, Germany.
245: Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
246: Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
247: Department of Neurology, Caen University Hospital, Caen, France.
248: University of Caen Normandy, Caen, France.
249: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
250: Landspitali University Hospital, Reykjavik, Iceland.
251: Survey Research Center, University of Michigan, Ann Arbor, MI, USA.
252: Department of Neurology, University of Virginia, Charlottesville, VA, USA.
253: Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
254: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

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.