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Abstract

We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 × 10−7). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 × 10−11; combined RR = 1.25; combined P = 1.8 × 10−15).

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Change history

  • 29 July 2009

    NOTE: In the version of this article initially published online, the name of author H.-Erich Wichmann was incorrectly given as Hans-E. Wichmann and this author's affiliation at the Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany, was missing. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

Complete study acknowledgments are listed in the Supplementary Note. The authors thank the studies' participants, staff and the funding agencies for their support.

Author information

Author notes

    • Emelia J Benjamin
    • , Kenneth M Rice
    • , Dan E Arking
    • , Arne Pfeufer
    • , Charlotte van Noord
    • , Albert V Smith
    • , Kathryn L Lunetta
    • , Susan R Heckbert
    • , Vilmundur Gudnason
    • , Alvaro Alonso
    • , Stefan Kääb
    • , Patrick T Ellinor
    •  & Jacqueline C M Witteman

    These authors contributed equally to this work.

Affiliations

  1. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Emelia J Benjamin
    • , Renate B Schnabel
    • , Ralph B D'Agostino Sr
    • , Christopher Newton-Cheh
    • , Martin G Larson
    • , Thomas J Wang
    • , Daniel Levy
    • , Ramachandran S Vasan
    • , Philip A Wolf
    •  & Kathryn L Lunetta
  2. Cardiology and Preventive Medicine Sections, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Emelia J Benjamin
    • , Daniel Levy
    •  & Ramachandran S Vasan
  3. Epidemiology Department, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Emelia J Benjamin
  4. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Kenneth M Rice
    •  & Thomas Lumley
  5. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Dan E Arking
    • , Georg B Ehret
    •  & Aravinda Chakravarti
  6. Department of Human Genetics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.

    • Arne Pfeufer
    •  & Thomas Meitinger
  7. Department of Human Genetics, Helmholtz Center Munich, German National Research Center for Environmental Health, Munich, Germany.

    • Arne Pfeufer
  8. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Charlotte van Noord
    • , Abbas Dehghan
    • , Jan Heeringa
    • , Fernando Rivadeneira
    • , Albert Hofman
    • , Bruno H Ch Stricker
    • , André G Uitterlinden
    • , Cornelia M van Duijn
    •  & Jacqueline C M Witteman
  9. Dutch Medicines Evaluation Board, The Hague, The Netherlands.

    • Charlotte van Noord
  10. Netherlands Consortium on Healthy Aging, Leiden, The Netherlands.

    • Charlotte van Noord
    •  & Jacqueline C M Witteman
  11. Icelandic Heart Association, Kópavogur, Iceland.

    • Albert V Smith
    • , Thor Aspelund
    • , Gudny Eiríksdottir
    •  & Vilmundur Gudnason
  12. Gutenberg Heart Study, Medical Clinic II (Cardiology), Johannes Gutenberg-University, Mainz, Germany.

    • Renate B Schnabel
  13. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Joshua C Bis
    •  & Bruce M Psaty
  14. Human Genetics Center and Division of Epidemiology, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Eric Boerwinkle
  15. Department of Medicine I, Ludwig Maximilians University Munich, Klinikum Grosshadern, Munich, Germany.

    • Moritz F Sinner
    • , Martina Mueller
    • , Gerhard Steinbeck
    •  & Stefan Kääb
  16. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Steven A Lubitz
  17. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Steven A Lubitz
    • , Christopher Newton-Cheh
    •  & Patrick T Ellinor
  18. Department of Mathematics & Statistics, Boston University, Boston, Massachusetts, USA.

    • Ralph B D'Agostino Sr
    •  & Martin G Larson
  19. University of Iceland, Reykjavik, Iceland.

    • Thor Aspelund
    •  & Vilmundur Gudnason
  20. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Christopher Newton-Cheh
  21. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.

    • Kristin D Marciante
    • , Bruce M Psaty
    •  & Nona Sotoodehnia
  22. Department of General Internal Medicine, University of Washington, Seattle, Washington, USA.

    • Kristin D Marciante
  23. Epidemiological Cardiology Research Center (EPICARE), Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

    • Elsayed Z Soliman
  24. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Fernando Rivadeneira
    • , Bruno H Ch Stricker
    •  & André G Uitterlinden
  25. Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Thomas J Wang
  26. Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

    • Daniel Levy
  27. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
    • , Nicholas L Smith
    •  & Susan R Heckbert
  28. Department of Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  29. Center for Health Studies, Group Health, Seattle, Washington, USA.

    • Bruce M Psaty
    •  & Susan R Heckbert
  30. Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Man Li
    • , W H Linda Kao
    •  & Anna Köttgen
  31. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

    • Alanna M Chamberlain
    •  & Alvaro Alonso
  32. Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA.

    • Tamara B Harris
    •  & Lenore J Launer
  33. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Jerome I Rotter
  34. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Sunil K Agarwal
  35. Inspectorate for Health Care, The Hague, The Netherlands.

    • Bruno H Ch Stricker
  36. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Ke Wang
    •  & Kathryn L Lunetta
  37. Seattle Epidemiologic Research and Information Center of the Department of Veterans Affairs Office of Research and Development, Seattle, Washington, USA.

    • Nicholas L Smith
  38. Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands.

    • André G Uitterlinden
  39. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Philip A Wolf
  40. Division of Cardiology, University of Washington, Seattle, Washington, USA.

    • Nona Sotoodehnia
  41. Institut für Epidemiologie, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Munich, Germany.

    • Martina Mueller
    •  & H-Erich Wichmann
  42. Institute of Medical Informatics, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.

    • Siegfried Perz
  43. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany.

    • H-Erich Wichmann
  44. Cardiac Arrhythmia Service, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Patrick T Ellinor

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Contributions

Statistical analyses: K.M.R., D.E.A., A.P., C.V.N., A.V.S., A.D., R.B.D., T.L., G.B.E., T.A., M.L., K.W., A.K., C.M.v.D., K.L.L. and M.M. Informatics: A.V.S., T.A., K.L.L. and M.M. Data preparation: T.A., K.W., A.C., K.L.L., V.G. and S.P. Sample collection and phenotype data collection: E.J.B., C.V.N., A.V.S., R.B.S., E.B., M.F.S., J.H., E.Z.S., T.J.W., G.E., D.L., B.M.P., A.M.C., A.H., R.S.V., S.K.A., P.A.W., S.R.H., V.G., A.A., S.K., T.M., S.P., G.S. and H.-E.W. Genotyping: A.V.S., M.F.S., T.A., G.E., J.I.R., V.G. and T.M.; Manuscript writing: E.J.B., K.M.R., D.E.A., S.A.L., K.L.L. and V.G. Review and revision of the manuscript: E.J.B., K.M.R., D.E.A., A.P., C.V.N., A.V.S., R.B.S., J.C.B., E.B., A.D., S.A.L., T.L., G.B.E., J.H., T.A., C.N.-C., M.G.L., K.D.M., E.Z.S., F.R., T.J.W., G.E., D.L., B.M.P., A.M.C., A.H., R.S.V., T.B.H., J.I.R., W.H.L.K., B.H.C.S., L.J.L., N.L.S., A.C., A.G.U., N.S., A.K., C.M.v.D., K.L.L., S.R.H., V.G., A.A., S.K., P.T.E., J.C.M.W., T.M., M.M., S.P., G.S. and H.-E.W. Intellectual input: E.J.B., K.M.R., D.E.A., R.B.S., M.G.L., K.L.L., S.R.H., S.K., P.T.E. and J.C.M.W. Study design: E.J.B., K.M.R., D.E.A., A.P., C.V.N., T.L., M.G.L., G.E., B.M.P., A.H., R.S.V., T.B.H., B.H.C.S., L.J.L., A.G.U., N.S., K.L.L., S.R.H., S.K., P.T.E., J.C.M.W., T.M., M.M., S.P., G.S. and H.-E.W. Study interpretation: E.J.B., K.M.R., C.V.N., R.B.S., J.C.B., E.B., T.L., R.S.V., W.H.L.K., K.L.L., S.R.H., A.A., S.K. and P.T.E. Study coordination: E.J.B., J.C.B., G.E., S.R.H., S.K. and P.T.E. Obtaining study funding: E.J.B., A.P., E.B., B.M.P., T.B.H., L.J.L., P.A.W., V.G., S.K., P.T.E., T.M., G.S. and H.-E.W.

Competing interests

Aravinda Chakravarti is a paid member of the Scientific Advisory Board of Affymetrix, a role that is managed by the Committee on Conflict of Interest of the Johns Hopkins University School of Medicine.

Corresponding authors

Correspondence to Emelia J Benjamin or Jacqueline C M Witteman.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–4, Supplementary Tables 1–4, Supplementary Note and Supplementary Methods

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DOI

https://doi.org/10.1038/ng.416

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