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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 M4,5, Okada Y6,7,8, Mishra A4,5, Rutten-Jacobs L3, Giese AK9, van der Laan SW10, Gretarsdottir S11, Anderson CD12,13,14, Chong M15, Adams HHH16,17, Ago T18, Almgren P19, Amouyel P20,21, Ay H13,22, Bartz TM23, Benavente OR24, Bevan S25, Boncoraglio GB26, Brown RD Jr27, Butterworth AS28,29, Carrera C30,31, Carty CL32,33, Chasman DI34,35, Chen WM36, Cole JW37, Correa A38, Cotlarciuc I39, Cruchaga C40,41, Danesh J28,42,43,44, de Bakker PIW45,46, DeStefano AL47,48, den Hoed M49, Duan Q50, Engelter ST51,52, Falcone GJ53,54, Gottesman RF55, Grewal RP56, Gudnason V57,58, Gustafsson S59, Haessler J60, Harris TB61, Hassan A62, Havulinna AS63,64, Heckbert SR65, Holliday EG66,67, Howard G68, Hsu FC69, Hyacinth HI70, Ikram MA16, Ingelsson E71,59, Irvin MR72, Jian X73, Jiménez-Conde J74, Johnson JA75,76, Jukema JW77, Kanai M6,7,78, Keene KL79,80, Kissela BM81, Kleindorfer DO81, Kooperberg C60, Kubo M82, Lange LA83, Langefeld CD84, Langenberg C85, Launer LJ86, Lee JM87, Lemmens R88,89, Leys D90, Lewis CM91,92, Lin WY28,93, Lindgren AG94,95, Lorentzen E96, Magnusson PK97, Maguire J98, Manichaikul A36, McArdle PF99, Meschia JF100, Mitchell BD99,101, Mosley TH102,103, Nalls MA104,105, Ninomiya T106, O'Donnell MJ15,107, Psaty BM108,65,109,110, Pulit SL45,111, Rannikmäe K112,113, Reiner AP65,114, Rexrode KM115, Rice K116, Rich SS36, Ridker PM34,35, Rost NS9,13, Rothwell PM117, Rotter JI118,119, Rundek T120, Sacco RL120, Sakaue S7,121, Sale MM122, Salomaa V63, Sapkota BR123, Schmidt R124, Schmidt CO125, Schminke U126, Sharma P39, Slowik A127, Sudlow CLM112,113, Tanislav C128, Tatlisumak T129,130, Taylor KD118,119, Thijs VNS131,132, Thorleifsson G11, Thorsteinsdottir U11, Tiedt S1, Trompet S133, Tzourio C5,134,135, van Duijn CM136,137, Walters M138, Wareham NJ85, Wassertheil-Smoller S139, Wilson JG140, Wiggins KL108, Yang Q47, Yusuf S15, Bis JC108, Pastinen T141, Ruusalepp A142,143,144, Schadt EE145, Koplev S145, Björkegren JLM145,146,147,144, Codoni V148,149, Civelek M122,150, Smith NL65,151,152, Trégouët DA148,149, Christophersen IE54,153,154, Roselli C54, Lubitz SA54,153, Ellinor PT54,153, Tai ES155, Kooner JS156, Kato N157, He J158, van der Harst P159, Elliott P160, Chambers JC161,162, Takeuchi F157, Johnson AD48,163, Sanghera DK123,164,165, Melander O19, Jern C166, Strbian D167,168, Fernandez-Cadenas I30,31, Longstreth WT Jr65,169, Rolfs A170, Hata J106, Woo D81, Rosand J12,13,14, Pare G15, Hopewell JC171, Saleheen D172, Stefansson K11,58, Worrall BB173, Kittner SJ37, Seshadri S48,174, Fornage M73,175, Markus HS3, Howson JMM28, Kamatani Y6,176, Debette S177,178, Dichgans M179,180,181, Malik R1, Chauhan G2, Traylor M3, Sargurupremraj M4,5, Okada Y6,7,8, Mishra A4,5, Rutten-Jacobs L3, Giese AK9, van der Laan SW10, Gretarsdottir S11, Anderson CD12,13,14, Chong M15, Adams HHH16,17, Ago T18, Almgren P19, Amouyel P20,21, Ay H13,22, Bartz TM23, Benavente OR24, Bevan S25, Boncoraglio GB26, Brown RD Jr27, Butterworth AS28,29, Carrera C30,31, Carty CL32,33, Chasman DI34,35, Chen WM36, Cole JW37, Correa A38, Cotlarciuc I39, Cruchaga C40,41, Danesh J28,42,43,44, de Bakker PIW45,46, DeStefano AL47,48, Hoed MD49, Duan Q50, Engelter ST51,52, Falcone GJ53,54, Gottesman RF55, Grewal RP56, Gudnason V57,58, Gustafsson S59, Haessler J60, Harris TB61, Hassan A62, Havulinna AS63,64, Heckbert SR65, Holliday EG66,67, Howard G68, Hsu FC69, Hyacinth HI70, Ikram MA16, Ingelsson E71,59, Irvin MR72, Jian X73, Jiménez-Conde J74, Johnson JA75,76, Jukema JW77, Kanai M6,7,78, Keene KL79,80, Kissela BM81, Kleindorfer DO81, Kooperberg C60, Kubo M82, Lange LA83, Langefeld CD84, Langenberg C85, Launer LJ86, Lee JM87, Lemmens R88,89, Leys D90, Lewis CM91,92, Lin WY28,93, Lindgren AG94,95, Lorentzen E96, Magnusson PK97, Maguire J98, Manichaikul A36, McArdle PF99, Meschia JF100, Mitchell BD99,101, Mosley TH102,103, Nalls MA104,105, Ninomiya T106, O'Donnell MJ15,107, Psaty BM108,65,109,110, Pulit SL45,111, Rannikmäe K112,113, Reiner AP65,114, Rexrode KM115, Rice K116, Rich SS36, Ridker PM34,35, Rost NS9,13, Rothwell PM117, Rotter JI118,119, Rundek T120, Sacco RL120, Sakaue S7,121, Sale MM122, Salomaa V63, Sapkota BR123, Schmidt R124, Schmidt CO125, Schminke U126, Sharma P39, Slowik A127, Sudlow CLM112,113, Tanislav C128, Tatlisumak T129,130, Taylor KD118,119, Thijs VNS131,132, Thorleifsson G11, Thorsteinsdottir U11, Tiedt S1, Trompet S133, Tzourio C5,134,135, van Duijn CM136,137, Walters M138, Wareham NJ85, Wassertheil-Smoller S139, Wilson JG140, Wiggins KL108, Yang Q47, Yusuf S15, Amin N16, Aparicio HS48,182, Arnett DK183, Attia J184, Beiser AS47,48, Berr C185, Buring JE34,35, Bustamante M186, Caso V187, Cheng YC99, Choi SH48,188, Chowhan A48,182, Cullell N31, Dartigues JF189,190, Delavaran H94,95, Delgado P191, Dörr M192,193, Engström G19, Ford I194, Gurpreet WS195, Hamsten A196,197, Heitsch L198, Hozawa A199, Ibanez L200, Ilinca A94,95, Ingelsson M201, Iwasaki M202, Jackson RD203, Jood K204, Jousilahti P63, Kaffashian S4,5, 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 CM215,216, Lioutas V48,217, Liu YM218, Lopez OL219, Makoto H220, Martinez-Majander N167, Matsuda K220, Minegishi N199, Montaner J30, Morris AP221,222, Muiño E31, Müller-Nurasyid M223,224,225, Norrving B94,95, Ogishima S199, Parati EA26, Peddareddygari LR56, Pedersen NL97,226, Pera J127, Perola M63,227, Pezzini A228, Pileggi S229, Rabionet R230, Riba-Llena I30, Ribasés M231, Romero JR48,182, Roquer J232,233, Rudd AG234,235, Sarin AP64,236, Sarju R195, Sarnowski C47,48, Sasaki M237, Satizabal CL48,182, Satoh M237, Sattar N238, Sawada N202, Sibolt G167, Sigurdsson Á239, Smith A240, Sobue K237, Soriano-Tárraga C233, Stanne T241, Stine OC242, Stott DJ243, Strauch K223,244, Takai T199, Tanaka H245,246, Tanno K237, Teumer A125, Tomppo L167, Torres-Aguila NP31, Touze E247,248, Tsugane S202, Uitterlinden AG249, Valdimarsson EM250, van der Lee SJ16, Völzke H125, Wakai K245, Weir D251, Williams SR252, Wolfe CDA234,235, Wong Q116, Xu H99, Yamaji T202, Sanghera DK123,164,165, Melander O19, Jern C166, Strbian D167,168, Fernandez-Cadenas I30,31, Longstreth WT Jr65,169, Rolfs A170, Hata J106, Woo D81, Rosand J12,13,14, Pare G15, Hopewell JC171, Saleheen D172, Stefansson K11,58, Worrall BB173, Kittner SJ37, Seshadri S48,174, Fornage M73,175, Markus HS3, Howson JMM28, Kamatani Y6,176, Debette S4,5, Dichgans M1,253,254; 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.

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