Letter | Published:

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Nature Genetics volume 49, pages 946952 (2017) | Download Citation

  • An Erratum to this article was published on 27 July 2017

This article has been updated

Abstract

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death1,2. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups3,4,5,6,7. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery8.

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Change history

  • 11 May 2017

    In the version of this article initially published online, the authors were incorrectly defined as members of the AFGen consortium in the author list. The members of the consortium are listed in the Supplementary Note. The error has been corrected in the print, PDF and HTML versions of this article.

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Acknowledgements

A full list of acknowledgments appears in the Supplementary Note.

Author information

Author notes

    • Ingrid E Christophersen
    • , Michiel Rienstra
    • , Carolina Roselli
    • , Xiaoyan Yin
    •  & Bastiaan Geelhoed

    These authors contributed equally to this work.

    • Emelia J Benjamin
    • , Toshihiro Tanaka
    • , Kathryn L Lunetta
    • , Steven A Lubitz
    •  & Patrick T Ellinor

    These authors jointly directed this work.

Affiliations

  1. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Ingrid E Christophersen
    • , Carolina Roselli
    • , Mark Chaffin
    • , Nathan R Tucker
    • , Derek Klarin
    • , J Gustav Smith
    • , Farid Radmanesh
    • , Seung Hoan Choi
    • , Lu-Chen Weng
    • , Natalia Rost
    • , Christopher D Anderson
    • , Christopher Newton-Cheh
    • , Jonathan Rosand
    • , Sekar Kathiresan
    • , Daniel I Chasman
    • , Steven A Lubitz
    •  & Patrick T Ellinor
  2. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Ingrid E Christophersen
    • , Nathan R Tucker
    • , Molong Li
    • , Lu-Chen Weng
    • , Sebastian Clauss
    • , Christopher Newton-Cheh
    • , Paul L Huang
    • , Steven A Lubitz
    •  & Patrick T Ellinor
  3. Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Rud, Norway.

    • Ingrid E Christophersen
  4. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Michiel Rienstra
    • , Bastiaan Geelhoed
    • , Yanick P Hagemeijer
    • , Niek Verweij
    • , Joylene E Siland
    •  & Pim van der Harst
  5. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Carolina Roselli
    •  & Martina Müller-Nurasyid
  6. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • Carolina Roselli
  7. NHLBI and Boston University's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Xiaoyan Yin
    • , Honghuang Lin
    • , Jared W Magnani
    • , Emelia J Benjamin
    •  & Kathryn L Lunetta
  8. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Xiaoyan Yin
    • , Honghuang Lin
    • , Qiong Yang
    •  & Kathryn L Lunetta
  9. Departments of Cardiovascular Medicine, Cellular and Molecular Medicine, Molecular Cardiology, and Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA.

    • John Barnard
    • , Jonathan D Smith
    • , David R Van Wagoner
    •  & Mina K Chung
  10. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Dan E Arking
  11. Icelandic Heart Association, Kopavogur, Iceland.

    • Albert V Smith
    •  & Vilmundur Gudnason
  12. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Albert V Smith
    •  & Vilmundur Gudnason
  13. Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Christine M Albert
    • , Paul M Ridker
    •  & Daniel I Chasman
  14. Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Christine M Albert
    •  & Paul M Ridker
  15. Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Nathan A Bihlmeyer
  16. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Siew-Kee Low
    •  & Yoichiro Kamatani
  17. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Peter E Weeke
    • , M Benjamin Shoemaker
    • , Joshua C Denny
    • , Christian Shaffer
    •  & Dan M Roden
  18. Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

    • Peter E Weeke
  19. Department of Medicine I, University Hospital Munich, Ludwig Maximilians University, Munich, Germany.

    • Martina Müller-Nurasyid
    • , Sebastian Clauss
    • , Moritz F Sinner
    •  & Stefan Kääb
  20. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.

    • Martina Müller-Nurasyid
    • , Sebastian Clauss
    • , Melanie Waldenberger
    • , Annette Peters
    • , Moritz F Sinner
    •  & Stefan Kääb
  21. Molecular Epidemiology and Cardiology, Clinical Sciences, Lund University, Lund, Sweden.

    • J Gustav Smith
  22. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Jennifer A Brody
    • , Joshua C Bis
    • , Bruce M Psaty
    •  & Traci M Bartz
  23. Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.

    • Maartje N Niemeijer
    • , Jan Heeringa
    • , Albert Hofman
    •  & Oscar H Franco
  24. Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.

    • Marcus Dörr
    •  & Stephan B Felix
  25. DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.

    • Marcus Dörr
    • , Stefan Weiss
    • , Alexander Teumer
    • , Uwe Völker
    •  & Stephan B Felix
  26. Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.

    • Stella Trompet
    •  & J Wouter Jukema
  27. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Jennifer Huffman
    •  & Caroline Hayward
  28. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

    • Stefan Gustafsson
    •  & Erik Ingelsson
  29. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Claudia Schurmann
    • , Yingchang Lu
    • , Erwin B Bottinger
    •  & Ruth J F Loos
  30. Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Claudia Schurmann
    • , Yingchang Lu
    •  & Ruth J F Loos
  31. Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.

    • Marcus E Kleber
    •  & Graciela Delgado
  32. Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere, Finland.

    • Leo-Pekka Lyytikäinen
    • , Ilkka Seppälä
    • , Jussi Hernesniemi
    •  & Terho Lehtimäki
  33. Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany.

    • Rainer Malik
    •  & Martin Dichgans
  34. Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo, São Paulo, Brazil.

    • Andrea R V R Horimoto
    •  & Jose E Krieger
  35. Department of Cardiovascular Medicine, Stanford University, Stanford, California, USA.

    • Marco Perez
  36. Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.

    • Juha Sinisalo
  37. Department of Medicine, University Hospital Basel, Basel, Switzerland.

    • Stefanie Aeschbacher
    •  & David Conen
  38. Cardiovascular Research Institute Basel, Basel, Switzerland.

    • Stefanie Aeschbacher
    •  & David Conen
  39. Population Health Research Institute, Hamilton, Ontario, Canada.

    • Sébastien Thériault
    • , Guillaume Paré
    •  & David Conen
  40. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

    • Sébastien Thériault
    •  & Guillaume Paré
  41. Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA.

    • Jie Yao
    • , Yii-Der Ida Chen
    • , Kent D Taylor
    • , Henry J Lin
    • , Xiuqing Guo
    •  & Jerome I Rotter
  42. Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Farid Radmanesh
    • , Christopher D Anderson
    •  & Jonathan Rosand
  43. Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany.

    • Stefan Weiss
    •  & Uwe Völker
  44. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

    • Alexander Teumer
  45. Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Rajat Deo
    •  & Daniel J Rader
  46. Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.

    • Svati H Shah
    •  & Albert Sun
  47. CTSU–Nuffield Department of Population Health, University of Oxford, Oxford, UK.

    • Jemma C Hopewell
  48. INSERM U1219 (Bordeaux Population Health Centre), Bordeaux, France.

    • Stephanie Debette
    •  & Ganesh Chauhan
  49. University of Bordeaux, Bordeaux, France.

    • Stephanie Debette
    •  & Ganesh Chauhan
  50. Department of Neurology, Bordeaux University Hospital, Bordeaux, France.

    • Stephanie Debette
  51. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Stephanie Debette
  52. Departments of Neurology and Public Health Science, University of Virginia Health System, Charlottesville, Virginia, USA.

    • Bradford B Worrall
  53. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Michiaki Kubo
  54. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Siegfried Perz
    • , Melanie Waldenberger
    • , Annette Peters
    •  & Jennifer Kriebel
  55. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
    • , Alex P Reiner
    •  & Susan R Heckbert
  56. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
    • , Nona Sotoodehnia
    •  & Susan R Heckbert
  57. Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.

    • Bruce M Psaty
    •  & Susan R Heckbert
  58. Department of Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  59. Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Jared W Magnani
    •  & Emelia J Benjamin
  60. Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland, USA.

    • Tamara B Harris
    •  & Lenore J Launer
  61. Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

    • Sandosh Padmanabhan
    •  & Alex P Reiner
  62. Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA.

    • Jeffrey Haessler
    •  & Charles Kooperberg
  63. Cardiovascular Health Research Unit, Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Traci M Bartz
  64. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Melanie Waldenberger
    •  & Jennifer Kriebel
  65. Institute of Human Genetics, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Peter Lichtner
  66. Institute of Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany.

    • Marina Arendt
    • , Lewin Eisele
    •  & Karl-Heinz Jöckel
  67. Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland.

    • Mika Kähönen
  68. University Institute of Clinical Chemistry, University of Bern, Bern, Switzerland.

    • Lorenz Risch
  69. Labormedizinisches Zentrum Dr. Risch, Schaan, Liechtenstein.

    • Lorenz Risch
  70. Heart Institute, University of São Paulo, São Paulo, Brazil.

    • Alfredo J Mansur
  71. German Center for Diabetes Research, Neuherberg, Germany.

    • Annette Peters
    •  & Jennifer Kriebel
  72. Division of Population Health Sciences, University of Dundee, Dundee, UK.

    • Blair H Smith
  73. Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.

    • Lars Lind
  74. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Stuart A Scott
  75. Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Erwin B Bottinger
  76. Department of Cardiology, Heart Hospital, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland.

    • Jussi Hernesniemi
    • , Markku Eskola
    •  & Kjell Nikus
  77. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Cecilia M Lindgren
    •  & Andrew P Morris
  78. Division of Cardiology, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada.

    • Jorge A Wong
  79. Boston VA Research Institute, Inc., Boston, Massachusetts, USA.

    • Jie Huang
  80. Department of Biostatistics, University of Liverpool, Liverpool, UK.

    • Andrew P Morris
  81. Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.

    • Ian Ford
  82. Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.

    • Lin Y Chen
  83. Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.

    • Roopinder K Sandhu
  84. Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Man Li
  85. Division of Nephrology and Hypertension, Internal Medicine, School of Medicine, University of Utah, Salt Lake City, Utah, USA.

    • Man Li
  86. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

    • Eric Boerwinkle
  87. Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.

    • Lars Lannfelt
  88. Acute Stroke Services, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Natalia Rost
  89. Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Archie Campbell
    •  & David Porteous
  90. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Patrik K Magnusson
    •  & Nancy L Pedersen
  91. Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Aberdeen, UK.

    • Lynne J Hocking
  92. Transplantation Laboratory, Medicum, University of Helsinki, Helsinki, Finland.

    • Efthymia Vlachopoulou
    •  & Marja-Liisa Lokki
  93. Department of Clinical Sciences, Lund University, Malmö, Sweden.

    • Marju Orho-Melander
    •  & Peter Almgren
  94. Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

    • Anders Hamsten
  95. Department of Medicine and Pharmacology, University of Illinois, Chicago, Illinois, USA.

    • Dawood Darbar
  96. Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

    • Peter W Macfarlane
  97. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Stefanie Heilmann-Heimbach
  98. Department of Genomics, Life and Brain Research Center, University of Bonn, Bonn, Germany.

    • Stefanie Heilmann-Heimbach
  99. Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Elsayed Z Soliman
  100. Department of Epidemiology and Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.

    • Andre G Uitterlinden
    •  & Bruno H Stricker
  101. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

    • Martin Dichgans
  102. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

    • Martin Dichgans
  103. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

    • Erik Ingelsson
  104. Department of Internal Medicine, Clinical Sciences, Lund University, Malmö, Sweden.

    • Olle Melander
  105. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos
  106. Department of Cardio-Thoracic Surgery, Heart Hospital, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland.

    • Jari Laurikka
  107. Laboratory of Genetics and Molecular Biology, Heart Institute, University of São Paulo, São Paulo, Brazil.

    • Alexandre Pereira
  108. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Alexandre Pereira
  109. Durrer Center for Cardiogenetic Research, Amsterdam, the Netherlands.

    • J Wouter Jukema
  110. Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.

    • J Wouter Jukema
  111. Institute for Translational Genomics and Population Sciences, Department of Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA.

    • Jerome I Rotter
  112. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.

    • Winfried März
  113. Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim and Augsburg, Germany.

    • Winfried März
  114. Inspectorate of Health Care, Utrecht, the Netherlands.

    • Bruno H Stricker
  115. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.

    • Alvaro Alonso
  116. Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Daniel I Chasman
  117. Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Emelia J Benjamin
  118. Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Toshihiro Tanaka
  119. Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.

    • Toshihiro Tanaka
  120. Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Steven A Lubitz
    •  & Patrick T Ellinor

Consortia

  1. METASTROKE Consortium of the ISGC

    A full list of members and affiliations appears in the Supplementary Note.

  2. Neurology Working Group of the CHARGE Consortium

    A full list of members and affiliations appears in the Supplementary Note.

  3. the AFGen Consortium

    A full list of members and affiliations appears in the Supplementary Note.

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Contributions

I.E.C., C.R., X.Y., T.T., K.L.L., E.J.B., S.A.L., M.R., B.G., and P.T.E. wrote and edited the manuscript. All authors contributed to and discussed the results and commented on the manuscript. GWAS and ExWAS analyses: A.V.S., N.A.B., M.M.-N., I.S., C.S., P.E.W., S.A., S. Thériault, J.A.B., J.C.B., H.L., J. Huffman, J.Y., X.G., F.R., M.N.N., D.E.A., G.P., S.-K.L., Y.K., M. Kähönen, A.C.P., A.R.H., J.S., L.-P.L., M.A., M.E.K., J.G.S., R.M., S.G., S. Trompet, M.D., S.W., J.A.W., D.I.C., M.V.P., Q.Y., T.B.H., M.F.S., J.S., D.R.v.W. Individual data set quality control and GWAS and ExWAS meta-analyses: I.E.C., K.L.L., C.R., X.Y., M.R., B.G., Y.P.H., N.V., J.E.S. Replication in METASTROKE and Neuro-CHARGE: Q.Y., J.C.H., S.D., G.C., B.B.W. Replication in UK Biobank: S.K., D.K., C.N.-C. Replication in BioBank Japan: S.-K.L., Y.K., M. Kubo, T.T. Replication in African-American population: R.D., D.J.R., S.H.S., A.S. CCAF eQTL analyses: J.B., M.K.C., D.v.W., J.D.S. Functional annotation: I.E.C., S.H.C., L.-C.W., M. Li, C.R., M.C., N.R.T., S.C. Pathway analyses: H.L.

Competing interests

P.T.E. is the principal investigator on a grant from Bayer HealthCare to the Broad Institute focused on the genetics and therapeutics of atrial fibrillation. The remaining authors have no disclosures.

Corresponding author

Correspondence to Patrick T Ellinor.

Integrated supplementary information

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    Supplementary Figures 1–12, Supplementary Tables 3–9, 12–16 and 21–29, and Supplementary Note.

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    Supplementary Tables

    Supplementary Tables 1, 2, 10, 11 and 17–20.

About this article

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DOI

https://doi.org/10.1038/ng.3843

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