Meta-Analysis

. 2018 Jun 11;50(9):1225-1233.

doi: 10.1038/s41588-018-0133-9.

Multi-ethnic genome-wide association study for atrial fibrillation

Carolina Roselli¹, Mark D Chaffin¹, Lu-Chen Weng^{1

2}, Stefanie Aeschbacher^{3

4}, Gustav Ahlberg^{5

6

7}, Christine M Albert⁸, Peter Almgren⁹, Alvaro Alonso¹⁰, Christopher D Anderson^{1

11}, Krishna G Aragam^{1

11}, Dan E Arking¹², John Barnard¹³, Traci M Bartz¹⁴, Emelia J Benjamin^{15

16

17}, Nathan A Bihlmeyer¹⁸, Joshua C Bis¹⁹, Heather L Bloom²⁰, Eric Boerwinkle²¹, Erwin B Bottinger^{22

23}, Jennifer A Brody¹⁹, Hugh Calkins²⁴, Archie Campbell²⁵, Thomas P Cappola²⁶, John Carlquist^{27

28}, Daniel I Chasman^{1

29}, Lin Y Chen³⁰, Yii-Der Ida Chen³¹, Eue-Keun Choi³², Seung Hoan Choi¹, Ingrid E Christophersen^{1

2

33}, Mina K Chung¹³, John W Cole^{34

35}, David Conen^{3

4

36}, James Cook³⁷, Harry J Crijns³⁸, Michael J Cutler²⁷, Scott M Damrauer^{39

40}, Brian R Daniels¹, Dawood Darbar⁴¹, Graciela Delgado⁴², Joshua C Denny⁴³, Martin Dichgans^{44

45

46}, Marcus Dörr^{47

48}, Elton A Dudink³⁸, Samuel C Dudley⁴⁹, Nada Esa⁵⁰, Tonu Esko^{1

51}, Markku Eskola⁵², Diane Fatkin^{53

54

55}, Stephan B Felix^{47

48}, Ian Ford⁵⁶, Oscar H Franco⁵⁷, Bastiaan Geelhoed⁵⁸, Raji P Grewal^{59

60}, Vilmundur Gudnason^{61

62}, Xiuqing Guo³¹, Namrata Gupta¹, Stefan Gustafsson⁶³, Rebecca Gutmann⁶⁴, Anders Hamsten⁶⁵, Tamara B Harris⁶⁶, Caroline Hayward⁶⁷, Susan R Heckbert^{68

69}, Jussi Hernesniemi^{52

70}, Lynne J Hocking⁷¹, Albert Hofman⁵⁷, Andrea R V R Horimoto⁷², Jie Huang⁷³, Paul L Huang², Jennifer Huffman⁶⁷, Erik Ingelsson^{63

74}, Esra Gucuk Ipek²⁴, Kaoru Ito⁷⁵, Jordi Jimenez-Conde^{76

77}, Renee Johnson⁵³, J Wouter Jukema^{78

79

80}, Stefan Kääb^{81

82}, Mika Kähönen⁸³, Yoichiro Kamatani⁸⁴, John P Kane⁸⁵, Adnan Kastrati^{82

86}, Sekar Kathiresan^{1

11}, Petra Katschnig-Winter⁸⁷, Maryam Kavousi⁵⁷, Thorsten Kessler⁸⁶, Bas L Kietselaer³⁸, Paulus Kirchhof^{88

89

90}, Marcus E Kleber⁴², Stacey Knight^{27

91}, Jose E Krieger⁷², Michiaki Kubo⁹², Lenore J Launer⁶⁶, Jari Laurikka⁹³, Terho Lehtimäki⁷⁰, Kirsten Leineweber⁹⁴, Rozenn N Lemaitre¹⁹, Man Li^{95

96}, Hong Euy Lim⁹⁷, Henry J Lin³¹, Honghuang Lin^{15

16}, Lars Lind⁹⁸, Cecilia M Lindgren⁹⁹, Marja-Liisa Lokki¹⁰⁰, Barry London⁶⁴, Ruth J F Loos^{22

101

102}, Siew-Kee Low⁸⁴, Yingchang Lu^{22

101}, Leo-Pekka Lyytikäinen⁷⁰, Peter W Macfarlane¹⁰³, Patrik K Magnusson¹⁰⁴, Anubha Mahajan⁹⁹, Rainer Malik⁴⁴, Alfredo J Mansur¹⁰⁵, Gregory M Marcus¹⁰⁶, Lauren Margolin¹, Kenneth B Margulies²⁶, Winfried März^{107

108}, David D McManus⁵⁰, Olle Melander¹⁰⁹, Sanghamitra Mohanty^{110

111}, Jay A Montgomery⁴³, Michael P Morley²⁶, Andrew P Morris³⁷, Martina Müller-Nurasyid^{81

82

112}, Andrea Natale^{110

111}, Saman Nazarian¹¹³, Benjamin Neumann⁸¹, Christopher Newton-Cheh^{1

11}, Maartje N Niemeijer⁵⁷, Kjell Nikus⁵², Peter Nilsson¹¹⁴, Raymond Noordam¹¹⁵, Heidi Oellers¹¹⁶, Morten S Olesen^{5

6

7}, Marju Orho-Melander⁹, Sandosh Padmanabhan¹¹⁷, Hui-Nam Pak¹¹⁸, Guillaume Paré^{36

119}, Nancy L Pedersen¹⁰⁴, Joanna Pera¹²⁰, Alexandre Pereira^{121

122}, David Porteous²⁵, Bruce M Psaty^{69

123}, Sara L Pulit^{1

124

125}, Clive R Pullinger⁸⁵, Daniel J Rader¹²⁶, Lena Refsgaard^{5

6

7}, Marta Ribasés^{127

128

129}, Paul M Ridker⁸, Michiel Rienstra⁵⁸, Lorenz Risch^{130

131}, Dan M Roden⁴³, Jonathan Rosand^{1

11}, Michael A Rosenberg^{11

132}, Natalia Rost^{1

133}, Jerome I Rotter¹³⁴, Samir Saba¹³⁵, Roopinder K Sandhu¹³⁶, Renate B Schnabel^{137

138}, Katharina Schramm^{81

112}, Heribert Schunkert^{82

86}, Claudia Schurman^{22

101}, Stuart A Scott¹³⁹, Ilkka Seppälä⁷⁰, Christian Shaffer⁴³, Svati Shah¹⁴⁰, Alaa A Shalaby^{135

141}, Jaemin Shim¹⁴², M Benjamin Shoemaker⁴³, Joylene E Siland⁵⁸, Juha Sinisalo¹⁴³, Moritz F Sinner^{81

82}, Agnieszka Slowik¹²⁰, Albert V Smith^{61

62}, Blair H Smith¹⁴⁴, J Gustav Smith^{1

145}, Jonathan D Smith¹³, Nicholas L Smith^{68

69}, Elsayed Z Soliman¹⁴⁶, Nona Sotoodehnia¹⁴⁷, Bruno H Stricker^{148

149}, Albert Sun¹⁴⁰, Han Sun¹³, Jesper H Svendsen^{5

7}, Toshihiro Tanaka¹⁵⁰, Kahraman Tanriverdi⁵⁰, Kent D Taylor³¹, Maris Teder-Laving⁵¹, Alexander Teumer^{48

151}, Sébastien Thériault^{36

119}, Stella Trompet^{78

115}, Nathan R Tucker^{1

2}, Arnljot Tveit^{33

152}, Andre G Uitterlinden¹⁴⁸, Pim Van Der Harst⁵⁸, Isabelle C Van Gelder⁵⁸, David R Van Wagoner¹³, Niek Verweij⁵⁸, Efthymia Vlachopoulou¹⁰⁰, Uwe Völker^{48

153}, Biqi Wang¹⁵⁴, Peter E Weeke^{5

43}, Bob Weijs³⁸, Raul Weiss¹⁵⁵, Stefan Weiss^{48

153}, Quinn S Wells⁴³, Kerri L Wiggins¹⁹, Jorge A Wong¹⁵⁶, Daniel Woo¹⁵⁷, Bradford B Worrall¹⁵⁸, Pil-Sung Yang¹¹⁸, Jie Yao³¹, Zachary T Yoneda⁴³, Tanja Zeller^{137

138}, Lingyao Zeng⁸⁶, Steven A Lubitz^{1

2

159}, Kathryn L Lunetta^{15

154}, Patrick T Ellinor^{160

161

162}

Affiliations

¹ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
³ University Hospital Basel, Basel, Switzerland.
⁴ Cardiovascular Research Institute Basel, Basel, Switzerland.
⁵ Laboratory for Molecular Cardiology, The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁶ The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸ Divisions of Preventive and Cardiovascular Medicine, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
⁹ Department of Clinical Sciences, Lund University, Malmo, Sweden.
¹⁰ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
¹¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹² McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Departments of Cardiovascular Medicine, Cellular and Molecular Medicine, Molecular Cardiology, and Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.
¹⁴ Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, USA.
¹⁵ NHLBI and Boston University's Framingham Heart Study, Framingham, MA, USA.
¹⁶ Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
¹⁷ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
¹⁸ Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁰ Division of Cardiology, Emory University and Atlanta VA Medical Center, Atlanta, GA, USA.
²¹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
²² The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²³ Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁴ Johns Hopkins University, Baltimore, MD, USA.
²⁵ Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
²⁶ Penn Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁷ Intermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA.
²⁸ Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT, USA.
²⁹ Divisions of Preventive Medicine and Genetics, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
³⁰ Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
³¹ Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
³² Seoul National University Hospital, Seoul, Korea.
³³ Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Drammen, Norway.
³⁴ Baltimore Veterans Affairs Medical Center, Department of Neurology, Baltimore, MD, USA.
³⁵ University of Maryland School of Medicine, Department of Neurology, Baltimore, MD, USA.
³⁶ Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
³⁷ Department of Biostatistics, University of Liverpool, Liverpool, UK.
³⁸ Maastricht University Medical Center+ and Cardiovascular Research Institute Maastricht, Department of Cardiology, Maastricht, The Netherlands.
³⁹ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁰ Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
⁴¹ University of Illinois Chicago, Chicago, IL, USA.
⁴² Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
⁴³ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴⁴ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
⁴⁵ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴⁶ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
⁴⁷ Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
⁴⁸ DZHK (German Centre for Cardiovascular Research), partner site: Greifswald, Greifswald, Germany.
⁴⁹ Cardiovascular Division and Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA.
⁵⁰ University of Massachusetts Medical School Worcester, Worcester, MA, USA.
⁵¹ Estonian Genome Center, University of Tartu, Tartu, Estonia.
⁵² Heart Center, Department of Cardiology, Tampere University Hospital, Finland and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
⁵³ Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
⁵⁴ St Vincent's Hospital, Darlinghurst, New South Wales, Australia.
⁵⁵ Faculty of Medicine, University of New South Wales, Kensington, New South Wales, Australia.
⁵⁶ Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
⁵⁷ Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁵⁸ Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁵⁹ Dept. of Neuroscience, Saint Francis Medical Center, Trenton, NJ, USA.
⁶⁰ School of Health and Medical Sciences, Seton Hall University, South Orange, NJ, USA.
⁶¹ Icelandic Heart Association, Kopavogur, Iceland.
⁶² Faculty of Medicine, University of Iceland, Reykavik, Iceland.
⁶³ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁶⁴ Division of Cardiovascular Medicine and Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA, USA.
⁶⁵ Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
⁶⁶ Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD, USA.
⁶⁷ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁶⁸ Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁶⁹ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁷⁰ Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
⁷¹ Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
⁷² Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo, São Paulo, Brazil.
⁷³ Boston VA Research Institute, Inc., Boston, MA, USA.
⁷⁴ Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁷⁵ Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁷⁶ Department of Neurology, Neurovascular Research Group IMIM-Hospital del Mar (Institut Hospital del Mar d'Investigacions Médiques), Barcelona, Spain.
⁷⁷ Universitat Autònoma de Barcelona, Medicine Department, Barcelona, Spain.
⁷⁸ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
⁷⁹ Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands.
⁸⁰ Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
⁸¹ Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University, Munich, Germany.
⁸² DZHK (German Centre for Cardiovascular Research), partner site: Munich Heart Alliance, Munich, Germany.
⁸³ Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
⁸⁴ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁸⁵ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
⁸⁶ Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany.
⁸⁷ Department of Neurology, Medical University of Graz, Graz, Austria.
⁸⁸ Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK.
⁸⁹ Sandwell and West Birmingham Hospitals NHS Trust and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
⁹⁰ AFNET, Muenster, Germany.
⁹¹ Department of Medicine, University of Utah, Salt Lake City, UT, USA.
⁹² RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁹³ Department of Cardio-Thoracic Surgery, Heart Center, Tampere University Hospital, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
⁹⁴ Dept. Disease Genomics, Bayer, Wuppertal, Germany.
⁹⁵ Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
⁹⁶ Division of Nephrology & Hypertension, Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT, USA.
⁹⁷ Korea University Guro Hospital, Seoul, Korea.
⁹⁸ Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
⁹⁹ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
¹⁰⁰ Transplantation Laboratory, Medicum, University of Helsinki, Helsinki, Finland.
¹⁰¹ The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁰² The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰³ Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
¹⁰⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁰⁵ Heart Institute, University of São Paulo, São Paulo, Brazil.
¹⁰⁶ Division of Cardiology, University of California, San Francisco, San Francisco, California, USA.
¹⁰⁷ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
¹⁰⁸ Synlab Academy, Synlab Services GmbH, Mannheim, Germany.
¹⁰⁹ Department of Internal Medicine, Clinical Sciences, Lund University, Malmo, Sweden.
¹¹⁰ Texas Cardiac Arrhythmia Institute, St David's Medical Center, Austin, TX, USA.
¹¹¹ Dell Medical School, Austin, TX, USA.
¹¹² Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹¹³ University of Pennsylvania, Philadelphia, PA, USA.
¹¹⁴ Department of Clinical Sciences, Lund University and Skåne University Hospital, Malmo, Sweden.
¹¹⁵ Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
¹¹⁶ Atrial Fibrillation NETwork, Muenster, Germany.
¹¹⁷ Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
¹¹⁸ Yonsei University Health System, Seoul, Korea.
¹¹⁹ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
¹²⁰ Department of Neurology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.
¹²¹ Laboratory of Genetics and Molecular Biology, Heart Institute, University of São Paulo, São Paulo, Brazil.
¹²² Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹²³ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.
¹²⁴ Department of Genetics, Center for Molecular Medicine, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
¹²⁵ Li Ka Shing Center for Health Information and Discovery, Big Data Institute, Oxford University, Oxford, UK.
¹²⁶ Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹²⁷ Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
¹²⁸ Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
¹²⁹ Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
¹³⁰ University Institute of Clinical Chemistry, University of Bern, Bern, Switzerland.
¹³¹ Labormedizinisches Zentrum Dr. Risch, Schaan, Liechtenstein.
¹³² University of Colorado School of Medicine, Aurora, CO, USA.
¹³³ J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA, USA.
¹³⁴ Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹³⁵ Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA.
¹³⁶ Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.
¹³⁷ Department of General and Interventional Cardiology, University Heart Centre Hamburg, Hamburg, Germany.
¹³⁸ DZHK (German Centre for Cardiovascular Research), partner site: Hamburg/Kiel/Lübeck, Hamburg, Germany.
¹³⁹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴⁰ Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁴¹ Cardiology Division, Pittsburgh VA Healthcare System, Pittsburgh, Pennsylvania, USA.
¹⁴² Korea University Anam Hospital, Seoul, Korea.
¹⁴³ Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.
¹⁴⁴ Division of Population Health Sciences, University of Dundee, Dundee, UK.
¹⁴⁵ Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
¹⁴⁶ Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston Salem, NC, USA.
¹⁴⁷ Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
¹⁴⁸ Department of Epidemiology and Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁴⁹ Inspectorate of Health Care, Utrecht, The Netherlands.
¹⁵⁰ Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.
¹⁵¹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹⁵² Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁵³ Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
¹⁵⁴ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁵⁵ Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH, USA.
¹⁵⁶ Division of Cardiology, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada.
¹⁵⁷ University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁵⁸ Departments of Neurology and Public Health Science, University of Virginia Health System, Charlottesville, VA, USA.
¹⁵⁹ Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA.
¹⁶⁰ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. ellinor@mgh.harvard.edu.
¹⁶¹ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. ellinor@mgh.harvard.edu.
¹⁶² Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA. ellinor@mgh.harvard.edu.

PMID: 29892015
PMCID: PMC6136836
DOI: 10.1038/s41588-018-0133-9

Meta-Analysis

Multi-ethnic genome-wide association study for atrial fibrillation

Carolina Roselli et al. Nat Genet. 2018.

. 2018 Jun 11;50(9):1225-1233.

doi: 10.1038/s41588-018-0133-9.

Authors

Affiliations

¹ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
³ University Hospital Basel, Basel, Switzerland.
⁴ Cardiovascular Research Institute Basel, Basel, Switzerland.
⁵ Laboratory for Molecular Cardiology, The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁶ The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸ Divisions of Preventive and Cardiovascular Medicine, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
⁹ Department of Clinical Sciences, Lund University, Malmo, Sweden.
¹⁰ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
¹¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹² McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Departments of Cardiovascular Medicine, Cellular and Molecular Medicine, Molecular Cardiology, and Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.
¹⁴ Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, USA.
¹⁵ NHLBI and Boston University's Framingham Heart Study, Framingham, MA, USA.
¹⁶ Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
¹⁷ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
¹⁸ Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁰ Division of Cardiology, Emory University and Atlanta VA Medical Center, Atlanta, GA, USA.
²¹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
²² The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²³ Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁴ Johns Hopkins University, Baltimore, MD, USA.
²⁵ Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
²⁶ Penn Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁷ Intermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA.
²⁸ Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT, USA.
²⁹ Divisions of Preventive Medicine and Genetics, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
³⁰ Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
³¹ Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
³² Seoul National University Hospital, Seoul, Korea.
³³ Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Drammen, Norway.
³⁴ Baltimore Veterans Affairs Medical Center, Department of Neurology, Baltimore, MD, USA.
³⁵ University of Maryland School of Medicine, Department of Neurology, Baltimore, MD, USA.
³⁶ Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
³⁷ Department of Biostatistics, University of Liverpool, Liverpool, UK.
³⁸ Maastricht University Medical Center+ and Cardiovascular Research Institute Maastricht, Department of Cardiology, Maastricht, The Netherlands.
³⁹ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁰ Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
⁴¹ University of Illinois Chicago, Chicago, IL, USA.
⁴² Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
⁴³ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴⁴ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
⁴⁵ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴⁶ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
⁴⁷ Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
⁴⁸ DZHK (German Centre for Cardiovascular Research), partner site: Greifswald, Greifswald, Germany.
⁴⁹ Cardiovascular Division and Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA.
⁵⁰ University of Massachusetts Medical School Worcester, Worcester, MA, USA.
⁵¹ Estonian Genome Center, University of Tartu, Tartu, Estonia.
⁵² Heart Center, Department of Cardiology, Tampere University Hospital, Finland and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
⁵³ Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
⁵⁴ St Vincent's Hospital, Darlinghurst, New South Wales, Australia.
⁵⁵ Faculty of Medicine, University of New South Wales, Kensington, New South Wales, Australia.
⁵⁶ Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
⁵⁷ Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁵⁸ Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁵⁹ Dept. of Neuroscience, Saint Francis Medical Center, Trenton, NJ, USA.
⁶⁰ School of Health and Medical Sciences, Seton Hall University, South Orange, NJ, USA.
⁶¹ Icelandic Heart Association, Kopavogur, Iceland.
⁶² Faculty of Medicine, University of Iceland, Reykavik, Iceland.
⁶³ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁶⁴ Division of Cardiovascular Medicine and Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA, USA.
⁶⁵ Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
⁶⁶ Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD, USA.
⁶⁷ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁶⁸ Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁶⁹ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁷⁰ Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
⁷¹ Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
⁷² Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo, São Paulo, Brazil.
⁷³ Boston VA Research Institute, Inc., Boston, MA, USA.
⁷⁴ Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁷⁵ Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁷⁶ Department of Neurology, Neurovascular Research Group IMIM-Hospital del Mar (Institut Hospital del Mar d'Investigacions Médiques), Barcelona, Spain.
⁷⁷ Universitat Autònoma de Barcelona, Medicine Department, Barcelona, Spain.
⁷⁸ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
⁷⁹ Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands.
⁸⁰ Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
⁸¹ Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University, Munich, Germany.
⁸² DZHK (German Centre for Cardiovascular Research), partner site: Munich Heart Alliance, Munich, Germany.
⁸³ Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
⁸⁴ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁸⁵ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
⁸⁶ Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany.
⁸⁷ Department of Neurology, Medical University of Graz, Graz, Austria.
⁸⁸ Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK.
⁸⁹ Sandwell and West Birmingham Hospitals NHS Trust and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
⁹⁰ AFNET, Muenster, Germany.
⁹¹ Department of Medicine, University of Utah, Salt Lake City, UT, USA.
⁹² RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁹³ Department of Cardio-Thoracic Surgery, Heart Center, Tampere University Hospital, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
⁹⁴ Dept. Disease Genomics, Bayer, Wuppertal, Germany.
⁹⁵ Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
⁹⁶ Division of Nephrology & Hypertension, Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT, USA.
⁹⁷ Korea University Guro Hospital, Seoul, Korea.
⁹⁸ Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
⁹⁹ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
¹⁰⁰ Transplantation Laboratory, Medicum, University of Helsinki, Helsinki, Finland.
¹⁰¹ The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁰² The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰³ Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
¹⁰⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁰⁵ Heart Institute, University of São Paulo, São Paulo, Brazil.
¹⁰⁶ Division of Cardiology, University of California, San Francisco, San Francisco, California, USA.
¹⁰⁷ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
¹⁰⁸ Synlab Academy, Synlab Services GmbH, Mannheim, Germany.
¹⁰⁹ Department of Internal Medicine, Clinical Sciences, Lund University, Malmo, Sweden.
¹¹⁰ Texas Cardiac Arrhythmia Institute, St David's Medical Center, Austin, TX, USA.
¹¹¹ Dell Medical School, Austin, TX, USA.
¹¹² Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹¹³ University of Pennsylvania, Philadelphia, PA, USA.
¹¹⁴ Department of Clinical Sciences, Lund University and Skåne University Hospital, Malmo, Sweden.
¹¹⁵ Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
¹¹⁶ Atrial Fibrillation NETwork, Muenster, Germany.
¹¹⁷ Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
¹¹⁸ Yonsei University Health System, Seoul, Korea.
¹¹⁹ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
¹²⁰ Department of Neurology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.
¹²¹ Laboratory of Genetics and Molecular Biology, Heart Institute, University of São Paulo, São Paulo, Brazil.
¹²² Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹²³ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.
¹²⁴ Department of Genetics, Center for Molecular Medicine, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
¹²⁵ Li Ka Shing Center for Health Information and Discovery, Big Data Institute, Oxford University, Oxford, UK.
¹²⁶ Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹²⁷ Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
¹²⁸ Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
¹²⁹ Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
¹³⁰ University Institute of Clinical Chemistry, University of Bern, Bern, Switzerland.
¹³¹ Labormedizinisches Zentrum Dr. Risch, Schaan, Liechtenstein.
¹³² University of Colorado School of Medicine, Aurora, CO, USA.
¹³³ J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA, USA.
¹³⁴ Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹³⁵ Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA.
¹³⁶ Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.
¹³⁷ Department of General and Interventional Cardiology, University Heart Centre Hamburg, Hamburg, Germany.
¹³⁸ DZHK (German Centre for Cardiovascular Research), partner site: Hamburg/Kiel/Lübeck, Hamburg, Germany.
¹³⁹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴⁰ Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁴¹ Cardiology Division, Pittsburgh VA Healthcare System, Pittsburgh, Pennsylvania, USA.
¹⁴² Korea University Anam Hospital, Seoul, Korea.
¹⁴³ Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.
¹⁴⁴ Division of Population Health Sciences, University of Dundee, Dundee, UK.
¹⁴⁵ Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
¹⁴⁶ Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston Salem, NC, USA.
¹⁴⁷ Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
¹⁴⁸ Department of Epidemiology and Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁴⁹ Inspectorate of Health Care, Utrecht, The Netherlands.
¹⁵⁰ Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.
¹⁵¹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹⁵² Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁵³ Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
¹⁵⁴ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁵⁵ Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH, USA.
¹⁵⁶ Division of Cardiology, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada.
¹⁵⁷ University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁵⁸ Departments of Neurology and Public Health Science, University of Virginia Health System, Charlottesville, VA, USA.
¹⁵⁹ Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA.
¹⁶⁰ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. ellinor@mgh.harvard.edu.
¹⁶¹ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. ellinor@mgh.harvard.edu.
¹⁶² Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA. ellinor@mgh.harvard.edu.

PMID: 29892015
PMCID: PMC6136836
DOI: 10.1038/s41588-018-0133-9

Abstract

Atrial fibrillation (AF) affects more than 33 million individuals worldwide¹ and has a complex heritability². We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

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Conflict of interest statement

Competing financial interests

Dr. Ellinor is the PI on a grant from Bayer to the Broad Institute focused on the genetics and therapeutics of atrial fibrillation. Dr. Psaty 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. Dr. Kirchhof receives research support from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies. Dr. Kirchhof is also listed as inventor on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). Dr. Leineweber is an employee of Bayer. The genotyping of participants in the Broad AF Study and the expression analysis of left atrial tissue samples were supported by a grant from Bayer to the Broad Institute. Dr. Nazarian is a consultant to Biosense Webster, Siemens, and Cardiosolv. Dr. Nazarian also receives research grants from NIH/NHLBI, Siemens, Biosense Webster, and Imricor. S. Kathiresan has received grant support from Bayer and Amarin; holds equity in San Therapeutics and Catabasis; and has received personal fees for participation in scientific advisory boards for Catabasis, Regeneron Genetics Center, Merck, Celera, Genomics PLC, Corvidia Therapeutics, Novo Ventures. S. Kathiresan also received personal fees from consulting services from Novartis, AstraZeneca, Alnylam, Eli Lilly Company, Leerink Partners, Merck, Noble Insights, Bayer, Ionis Pharmaceuticals, Novo Ventures, Haug Partners LLC. Genetic Modifiers Newco, Inc. Dr. Lubitz receives sponsored research support from Bristol Myers Squibb, Bayer, Biotronik, and Boehringer Ingelheim, and has consulted for St. Jude Medical / Abbott and Quest Diagnostics. The remaining authors have no disclosures.

Figures

**Figure 1.. Study and analysis flowchart**
Top, overview of the participating studies, number of AF cases and referents, and the percent of samples imputed with each reference panel. Middle, summary of the primary analyses and the newly discovered loci for AF. Bottom, overview of the secondary analyses to evaluate AF risk variants and loci.

**Figure 2.. Manhattan plot of combined-ancestry meta-analysis**
The plot shows 67 novel (red) and 27 known (blue) genetic loci associated with AF at a significance level of P < 1×10⁻⁸ (dashed line), for the combined-ancestry meta-analysis (n=588,190). The significance level accounts for multiple testing of independent variants with MAF ≥0.1% using a Bonferroni correction. P-values (two-sided) were derived from a meta-analysis using a fixed effects model with an inverse-variance weighted approach. The y-axis has a break between –log10(P) of 30 and 510 to emphasize the novel loci

**Figure 3.. Volcano plot of transcriptome-wide analysis from human heart tissues**
The plots show the results from the transcriptome-wide analysis based on left ventricle (a, n=190) and right atrial appendage (b, n=159) tissue from GTEx, calculated with the MetaXcan method based on the combined-ancestry summary level results (n=588,190). Each plotted point represents the association results for an individual gene. The x-axis shows the effect size for associations of predicted gene expression and AF risk for each tested gene. The y-axis shows the –log10(P) for the associations per gene. Genes with positive effect (red) showed an association of increased predicted gene expression with AF risk. Genes with negative effect (blue) showed an association of decreased predicted gene expression with AF risk. The highlighted genes are significant after Bonferroni correction for all tested genes and tissues with a P-value < 5.36×10^-6. The result for one gene for right atrial appendage (b) is not shown (*SNX4*, Effect = 6.94, P = 0.2).

**Figure 4.. Cross-trait associations of AF risk variants with AF risk factors in the UK Biobank**
The heatmap shows associations of novel and known sentinel variants at AF risk loci from the combined-ancestry meta-analysis. Shown are variants and phenotypes with significant associations after correcting for 12 phenotypes via Bonferroni with P < 4.17×10^-3. P-values (two-sided) were derived from linear and logistic regression models. Listed next to each trait is the number of cases for binary traits or total sample size for quantitative traits. Hierarchical clustering was performed on a variant level using the complete linkage method based on Euclidian distance. Coloring represents Z-scores for each respective trait or disease, oriented toward the AF risk allele. Red indicates an increase in the trait or disease risk while blue indicates a decrease in the trait or disease risk. Abbreviations, BMI, body-mass index, CAD, coronary artery disease, PVD, pulmonary vascular disease.

See this image and copyright information in PMC

References

1. Chugh SS et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 129, 837–47 (2014). - PMC - PubMed
1. Lubitz SA et al. Association between familial atrial fibrillation and risk of new-onset atrial fibrillation. JAMA 304, 2263–9 (2010). - PMC - PubMed
1. January CT et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary. J. Am. Coll. Cardiol. 64, (2014). - PubMed
1. Benjamin EJ et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat. Genet. 41, 879–81 (2009). - PMC - PubMed
1. Ellinor PT et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat. Genet. 44, 670–5 (2012). - PMC - PubMed

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Multi-ethnic genome-wide association study for atrial fibrillation

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Multi-ethnic genome-wide association study for atrial fibrillation

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