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

doi:10.1038/s41588-018-0058-3

Meta-Analysis

. 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

Rainer Malik^#¹, Ganesh Chauhan^#², Matthew Traylor^#³, Muralidharan Sargurupremraj^#^{4

5}, Yukinori Okada^#^{6

7

8}, Aniket Mishra^{4

5}, Loes Rutten-Jacobs³, Anne-Katrin Giese⁹, Sander W van der Laan¹⁰, Solveig Gretarsdottir¹¹, Christopher D Anderson^{12

13

14}, Michael Chong¹⁵, Hieab H H Adams^{16

17}, Tetsuro Ago¹⁸, Peter Almgren¹⁹, Philippe Amouyel^{20

21}, Hakan Ay^{13

22}, Traci M Bartz²³, Oscar R Benavente²⁴, Steve Bevan²⁵, Giorgio B Boncoraglio²⁶, Robert D Brown Jr²⁷, Adam S Butterworth^{28

29}, Caty Carrera^{30

31}, Cara L Carty^{32

33}, Daniel I Chasman^{34

35}, Wei-Min Chen³⁶, John W Cole³⁷, Adolfo Correa³⁸, Ioana Cotlarciuc³⁹, Carlos Cruchaga^{40

41}, John Danesh^{28

42

43

44}, Paul I W de Bakker^{45

46}, Anita L DeStefano^{47

48}, Marcel den Hoed⁴⁹, Qing Duan⁵⁰, Stefan T Engelter^{51

52}, Guido J Falcone^{53

54}, Rebecca F Gottesman⁵⁵, Raji P Grewal⁵⁶, Vilmundur Gudnason^{57

58}, Stefan Gustafsson⁵⁹, Jeffrey Haessler⁶⁰, Tamara B Harris⁶¹, Ahamad Hassan⁶², Aki S Havulinna^{63

64}, Susan R Heckbert⁶⁵, Elizabeth G Holliday^{66

67}, George Howard⁶⁸, Fang-Chi Hsu⁶⁹, Hyacinth I Hyacinth⁷⁰, M Arfan Ikram¹⁶, Erik Ingelsson^{71

59}, Marguerite R Irvin⁷², Xueqiu Jian⁷³, Jordi Jiménez-Conde⁷⁴, Julie A Johnson^{75

76}, J Wouter Jukema⁷⁷, Masahiro Kanai^{6

7

78}, Keith L Keene^{79

80}, Brett M Kissela⁸¹, Dawn O Kleindorfer⁸¹, Charles Kooperberg⁶⁰, Michiaki Kubo⁸², Leslie A Lange⁸³, Carl D Langefeld⁸⁴, Claudia Langenberg⁸⁵, Lenore J Launer⁸⁶, Jin-Moo Lee⁸⁷, Robin Lemmens^{88

89}, Didier Leys⁹⁰, Cathryn M Lewis^{91

92}, Wei-Yu Lin^{28

93}, Arne G Lindgren^{94

95}, Erik Lorentzen⁹⁶, Patrik K Magnusson⁹⁷, Jane Maguire⁹⁸, Ani Manichaikul³⁶, Patrick F McArdle⁹⁹, James F Meschia¹⁰⁰, Braxton D Mitchell^{99

101}, Thomas H Mosley^{102

103}, Michael A Nalls^{104

105}, Toshiharu Ninomiya¹⁰⁶, Martin J O'Donnell^{15

107}, Bruce M Psaty^{108

65

109

110}, Sara L Pulit^{45

111}, Kristiina Rannikmäe^{112

113}, Alexander P Reiner^{65

114}, Kathryn M Rexrode¹¹⁵, Kenneth Rice¹¹⁶, Stephen S Rich³⁶, Paul M Ridker^{34

35}, Natalia S Rost^{9

13}, Peter M Rothwell¹¹⁷, Jerome I Rotter^{118

119}, Tatjana Rundek¹²⁰, Ralph L Sacco¹²⁰, Saori Sakaue^{7

121}, Michele M Sale¹²², Veikko Salomaa⁶³, Bishwa R Sapkota¹²³, Reinhold Schmidt¹²⁴, Carsten O Schmidt¹²⁵, Ulf Schminke¹²⁶, Pankaj Sharma³⁹, Agnieszka Slowik¹²⁷, Cathie L M Sudlow^{112

113}, Christian Tanislav¹²⁸, Turgut Tatlisumak^{129

130}, Kent D Taylor^{118

119}, Vincent N S Thijs^{131

132}, Gudmar Thorleifsson¹¹, Unnur Thorsteinsdottir¹¹, Steffen Tiedt¹, Stella Trompet¹³³, Christophe Tzourio^{5

134

135}, Cornelia M van Duijn^{136

137}, Matthew Walters¹³⁸, Nicholas J Wareham⁸⁵, Sylvia Wassertheil-Smoller¹³⁹, James G Wilson¹⁴⁰, Kerri L Wiggins¹⁰⁸, Qiong Yang⁴⁷, Salim Yusuf¹⁵; AFGen Consortium; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium; International Genomics of Blood Pressure (iGEN-BP) Consortium; INVENT Consortium; STARNET; Joshua C Bis¹⁰⁸, Tomi Pastinen¹⁴¹, Arno Ruusalepp^{142

143

144}, Eric E Schadt¹⁴⁵, Simon Koplev¹⁴⁵, Johan L M Björkegren^{145

146

147

144}, Veronica Codoni^{148

149}, Mete Civelek^{122

150}, Nicholas L Smith^{65

151

152}, David A Trégouët^{148

149}, Ingrid E Christophersen^{54

153

154}, Carolina Roselli⁵⁴, Steven A Lubitz^{54

153}, Patrick T Ellinor^{54

153}, E Shyong Tai¹⁵⁵, Jaspal S Kooner¹⁵⁶, Norihiro Kato¹⁵⁷, Jiang He¹⁵⁸, Pim van der Harst¹⁵⁹, Paul Elliott¹⁶⁰, John C Chambers^{161

162}, Fumihiko Takeuchi¹⁵⁷, Andrew D Johnson^{48

163}; 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; Dharambir K Sanghera^{123

164

165}, Olle Melander¹⁹, Christina Jern¹⁶⁶, Daniel Strbian^{167

168}, Israel Fernandez-Cadenas^{30

31}, W T Longstreth Jr^{65

169}, Arndt Rolfs¹⁷⁰, Jun Hata¹⁰⁶, Daniel Woo⁸¹, Jonathan Rosand^{12

13

14}, Guillaume Pare¹⁵, Jemma C Hopewell¹⁷¹, Danish Saleheen¹⁷², Kari Stefansson^#^{11

58}, Bradford B Worrall^#¹⁷³, Steven J Kittner^#³⁷, Sudha Seshadri^#^{48

174}, Myriam Fornage^#^{73

175}, Hugh S Markus^#³, Joanna M M Howson^#²⁸, Yoichiro Kamatani^#^{6

176}, Stephanie Debette^#^{177

178}, Martin Dichgans^#^{179

180

181}

Collaborators, Affiliations

Collaborators

Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten-Jacobs, Anne-Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab H H Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown Jr, Adam S Butterworth, Caty Carrera, Cara L Carty, Daniel I Chasman, Wei-Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul I W de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Jeffrey Haessler, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Susan R Heckbert, Elizabeth G Holliday, George Howard, Fang-Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez-Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Charles Kooperberg, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin-Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei-Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O'Donnell, Bruce M Psaty, Sara L Pulit, Kristiina Rannikmäe, Alexander P Reiner, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Paul M Ridker, Natalia S Rost, Peter M Rothwell, Jerome I Rotter, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie L M Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent N S Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Stella Trompet, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil-Smoller, James G Wilson, Kerri L Wiggins, Qiong Yang, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu-Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean-François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez-Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller-Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba-Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti-Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano-Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres-Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles D A Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernandez-Cadenas, W T Longstreth Jr, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna M M Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans

Affiliations

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.

^# Contributed equally.

PMID: 29531354
PMCID: PMC5968830
DOI: 10.1038/s41588-018-0058-3

Meta-Analysis

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

Rainer Malik et al. Nat Genet. 2018 Apr.

. 2018 Apr;50(4):524-537.

doi: 10.1038/s41588-018-0058-3. Epub 2018 Mar 12.

Authors

Collaborators

Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten-Jacobs, Anne-Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab H H Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown Jr, Adam S Butterworth, Caty Carrera, Cara L Carty, Daniel I Chasman, Wei-Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul I W de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Jeffrey Haessler, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Susan R Heckbert, Elizabeth G Holliday, George Howard, Fang-Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez-Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Charles Kooperberg, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin-Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei-Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O'Donnell, Bruce M Psaty, Sara L Pulit, Kristiina Rannikmäe, Alexander P Reiner, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Paul M Ridker, Natalia S Rost, Peter M Rothwell, Jerome I Rotter, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie L M Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent N S Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Stella Trompet, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil-Smoller, James G Wilson, Kerri L Wiggins, Qiong Yang, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu-Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean-François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez-Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller-Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba-Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti-Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano-Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres-Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles D A Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernandez-Cadenas, W T Longstreth Jr, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna M M Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans

Affiliations

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.

^# Contributed equally.

PMID: 29531354
PMCID: PMC5968830
DOI: 10.1038/s41588-018-0058-3

Erratum in

Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.
Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HHH, Ago T, Almgren P, Amouyel P, Ay H, Bartz TM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD Jr, Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PIW, DeStefano AL, den Hoed M, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert SR, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Ingelsson E, Irvin MR, Jian X, Jiménez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange LA, Langefeld CD, Langenberg C, Launer LJ, Lee JM, Lemmens R, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Ninomiya T, O'Donnell MJ, Psaty BM, Pulit SL, Rannikmäe K, Reiner AP, Rexrode KM, Rice K, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rotter JI, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt CO, Sc… See abstract for full author list ➔ Malik R, et al. Nat Genet. 2019 Jul;51(7):1192-1193. doi: 10.1038/s41588-019-0449-0. Nat Genet. 2019. PMID: 31160810

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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Conflict of interest statement

Competing interests

S. Gretarsdottir, G.T., U.T., and K.S. are all employees of deCODE Genetics/Amgen, Inc. M.A.N. is an employee of Data Tecnica International. 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. S.A.L. receives sponsored research support from Bayer HealthCare, Biotronik, and Boehringer Ingelheim, and has consulted for St. Jude Medical and Quest Diagnostics. E.I. is a scientific advisor for Precision Wellness, Cellink and Olink Proteomics for work unrelated to the present project. B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. The remaining authors have no disclosures.

Figures

**Fig. 1. MEGASTROKE study design**
Variants were retained that passed central quality control (QC) criteria (Methods). The numbers of cases and controls are listed for each ancestry group. HRC, Haplotype Reference Consortium; imp, measure of imputation quality (Methods); FE, fixed effects; EUR, European ancestry; AFR, African ancestry; EAS, East Asian ancestry; SAS, South Asian ancestry; ASN, mixed Asian ancestry; LAT, Latin American ancestry; P_het, heterogeneity P value; PP_het, posterior probability of heterogeneity. *The ASN and LAT ancestries were composed of a single study and hence did not require ancestry-specific meta-analysis.

**Fig. 2. Association results of the transancestral GWAS meta-analysis and the prespecified ancestry-specific meta-analysis in European samples**
Shown are novel (red) and known (black) genetic loci associated with any stroke or stroke subtypes. Top, Manhattan plot from the MANTRA transancestral GWAS meta-analysis for any stroke. The dotted line marks the threshold of statistical significance (log₁₀(BF) >6.0).

**Fig. 3. Genetic overlap between stroke and related vascular traits at the 32 genome-wide-significant loci for stroke**
a, Association results from the look-ups in published GWAS data for related vascular traits. Symbol sizes reflect P values for association with the related trait. b, Venn diagram. Loci reaching genome-wide significance for association with stroke subtypes are marked with a dagger symbol (for CES), underlined (for LAS), or marked with an asterisk (for SVS). Novel loci are in bold. *SH3PXD2A, WNT2B, PDE3A*, and *OBFC1* have previously been associated with AF *(SH3PXD2A)*, or diastolic *(WNT2B* and PDE3A)^, or systolic *(OBFC1)* BP, but the respective lead SNPs were in low LD (r² <0.1 in the 1000G cosmopolitan panel) with variants associated with stroke in the current GWAS. MRI, magnetic resonance imaging; IMT, intima-media thickness; LDL, low-density lipoprotein; HDL, high-density lipoprotein. The lead variant for *TBX3* is not included in the original datasets for BP traits (SBP and DBP). Results are based on a perfect proxy SNP (rs35432, r² = 1 in the European 1000G phase 3 reference).

**Fig. 4. Shared genetic contribution between stroke and related vascular traits**
Contributions determined by weighted genetic risk scores (wGRS, top) and LD-score regression analysis (bottom). Effect sizes and significance levels are represented by color and symbol size. β, wGRS effect size; R(g), genetic correlation. DBP, diastolic blood pressure; SBP, systolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure; HTN, hypertension, TGL, triglyceride level. Sample sizes for related vascular traits are displayed in Supplementary Table 12. NS, nonsignificant.

**Fig. 5. Connection between stroke risk genes and approved drugs for antithrombotic therapy**
Shown are the connections among lead SNPs at stroke risk loci, biological stroke risk genes, and individual targeted drugs. Lead SNPs reaching suggestive evidence for association (MANTRA transancestral meta-analysis log₁₀(BF) >5) are shown in gray.

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References

1. GBD 2015 DALYs and HALE Collaborators. Global regional and national disability-adjusted life-years (DALYs) for 315 diseases injuries and healthy life expectancy (HALE) 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1603–1658. - PMC - PubMed
1. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality cause-specific mortality for 249 causes of death 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1459–1544. - PMC - PubMed
1. Gudbjartsson DF, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–357. - PubMed
1. Gudbjartsson DF, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet. 2009;41:876–878. - PMC - PubMed
1. International Stroke Genetics Consortium (ISGC) et al. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet. 2012;44:328–333. - PMC - PubMed

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[1] GBD 2015 DALYs and HALE Collaborators. Global regional and national disability-adjusted life-years (DALYs) for 315 diseases injuries and healthy life expectancy (HALE) 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1603–1658. - PMC - PubMed

[2] GBD 2015 DALYs and HALE Collaborators. Global regional and national disability-adjusted life-years (DALYs) for 315 diseases injuries and healthy life expectancy (HALE) 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1603–1658. - PMC - PubMed

[3] GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality cause-specific mortality for 249 causes of death 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1459–1544. - PMC - PubMed

[4] GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality cause-specific mortality for 249 causes of death 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1459–1544. - PMC - PubMed

[5] Gudbjartsson DF, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–357. - PubMed

[6] Gudbjartsson DF, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–357. - PubMed

[7] Gudbjartsson DF, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet. 2009;41:876–878. - PMC - PubMed

[8] Gudbjartsson DF, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet. 2009;41:876–878. - PMC - PubMed

[9] International Stroke Genetics Consortium (ISGC) et al. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet. 2012;44:328–333. - PMC - PubMed

[10] International Stroke Genetics Consortium (ISGC) et al. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet. 2012;44:328–333. - PMC - PubMed

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

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

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