Letter | Published:

Common variants in KCNN3 are associated with lone atrial fibrillation

Nature Genetics 42, 240–244 (2010) | Download Citation

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Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 × 10−12), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40–1.64; P = 1.83 × 10−21). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

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Acknowledgements

Acknowledgements are contained in the Supplementary Note.

Author information

    • Georg B Ehret

    Present address: Cardiology Center, Geneva University Hospital, Geneva, Switzerland.

    • Patrick T Ellinor
    • , Kathryn L Lunetta
    • , Nicole L Glazer
    • , Arne Pfeufer
    • , Alvaro Alonso
    • , Mina K Chung
    • , Moritz F Sinner
    • , Jacqueline C M Witteman
    • , John Barnard
    • , Dan E Arking
    • , Emelia J Benjamin
    • , Susan R Heckbert
    •  & Stefan Kääb

    These authors contributed equally to this work.

Affiliations

  1. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Patrick T Ellinor
    • , Steven A Lubitz
    • , Seiko Makino
    • , David J Milan
    •  & Christopher Newton-Cheh

  2. Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Patrick T Ellinor
    •  & David J Milan

  3. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Patrick T Ellinor
    •  & Christopher Newton-Cheh

  4. Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA.

    • Kathryn L Lunetta
    •  & Ke Wang

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

    • Kathryn L Lunetta
    • , Renate B Schnabel
    • , Thomas J Wang
    • , Ramachandran S Vasan
    •  & Emelia J Benjamin

  6. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Nicole L Glazer

  7. Institute of Human Genetics, Klinikum Rechts der Isar Technische Universität München, Munich, Germany.

    • Arne Pfeufer
    •  & Thomas Meitinger

  8. Institute of Human Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany.

    • Arne Pfeufer
    •  & Thomas Meitinger

  9. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

    • Alvaro Alonso

  10. Department of Cardiovascular Medicine, Heart and Vascular Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Mina K Chung
    • , David R Van Wagoner
    •  & Stanley L Hazen

  11. Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.

    • Moritz F Sinner
    • , Martina Mueller
    • , Britt-M Beckmann
    • , Gerhard Steinbeck
    •  & Stefan Kääb

  12. Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Paul I W de Bakker

  13. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Paul I W de Bakker
    •  & Christopher Newton-Cheh

  14. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Martina Mueller
    •  & H-Erich Wichmann

  15. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • Martina Mueller
    •  & H-Erich Wichmann

  16. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Steven A Lubitz

  17. Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • Ervin Fox

  18. Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Dawood Darbar

  19. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Nicholas L Smith
    •  & Susan R Heckbert

  20. Seattle Epidemiologic Research and Information Center of the Department of Veterans Affairs Office of Research and Development, Seattle, Washington, USA.

    • Nicholas L Smith

  21. Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Jonathan D Smith

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

    • Elsayed Z Soliman

  23. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Kenneth M Rice

  24. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Charlotte van Noord
    • , Bruno H Ch Stricker
    • , Albert Hofman
    • , André G Uitterlinden
    •  & Jacqueline C M Witteman

  25. Dutch Medicines Evaluation Board, The Hague, The Netherlands.

    • Charlotte van Noord

  26. Netherlands Consortium on Healthy Aging (NCHA), Leiden, The Netherlands.

    • Charlotte van Noord
    • , Bruno H Ch Stricker
    • , Albert Hofman
    • , André G Uitterlinden
    •  & Jacqueline C M Witteman

  27. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Georg B Ehret
    • , Aravinda Chakravarti
    •  & Dan E Arking

  28. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Jerome I Rotter

  29. Icelandic Heart Association, Kópavogur, Iceland.

    • Albert V Smith
    •  & Vilmundur Gudnason

  30. University of Iceland, Reykjavik, Iceland.

    • Albert V Smith
    •  & Vilmundur Gudnason

  31. Laboratory of Epidemiology, Demography and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA.

    • Lenore J Launer
    •  & Tamara B Harris

  32. Estonian Biocenter, Genotyping Core Facility, Tartu, Estonia.

    • Mari Nelis
    • , Tõnu Esko
    •  & Andres Metspalu

  33. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.

    • Mari Nelis
    • , Tõnu Esko
    •  & Andres Metspalu

  34. Institute for Biological and Medical Imaging, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Siegfried Perz

  35. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Tõnu Esko
    •  & Andres Metspalu

  36. Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Anna Köttgen
    • , Man Li
    •  & W H Linda Kao

  37. Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany.

    • Susanne Moebus

  38. Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Christopher Newton-Cheh
    •  & Thomas J Wang

  39. Department of Cardiology, West German Heart Center Essen, University Duisburg-Essen, Essen, Germany.

    • Stefan Möhlenkamp

  40. Section of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ramachandran S Vasan

  41. Section of Cardiology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ramachandran S Vasan

  42. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Markus M Nöthen

  43. Department of Genomics, Life and Brain Center Bonn, Bonn, Germany.

    • Markus M Nöthen

  44. Cardiovascular Division, Brigham and Woman's Hospital, Boston, Massachusetts, USA.

    • Calum A MacRae

  45. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Bruno H Ch Stricker
    •  & André G Uitterlinden

  46. Inspectorate for Health Care, The Hague, The Netherlands.

    • Bruno H Ch Stricker

  47. Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Bruno H Ch Stricker

  48. Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

    • Daniel Levy

  49. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Eric Boerwinkle

  50. Institute for Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Eric Boerwinkle

  51. Scripps Translational Science Institute, The Scripps Research Institute, Scripps Health, La Jolla, California, USA.

    • Eric J Topol

  52. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty

  53. Group Health Research Institute, Group Health, Seattle, Washington, USA.

    • Bruce M Psaty
    •  & Susan R Heckbert

  54. Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Dan M Roden

  55. Klinikum Grosshadern, Munich, Germany.

    • H-Erich Wichmann

  56. Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • John Barnard

  57. Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USA.

    • Emelia J Benjamin

  58. Cardiology and Preventive Medicine Division, Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.

    • Emelia J Benjamin

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Contributions

Study concept and design: P.T.E., K.L.L., N.L.G., A.P., M.K.C., A.A., J.C.M.W., D.E.A., E.J.B., S.R.H. and S.K.

Acquisition of data: P.T.E., K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., P.I.W.d.B., M.M., S.A.L., E.F., D.D., N.L.S., J.D.S., R.B.S., E.Z.S., K.M.R., D.R.V.W., B.-M.B, C.v.N., K.W., G.B.E., J.I.R., S.L.H., G.S., A.V.S., L.J.L., T.B.H., S.M., M.N., D.J.M., S.P., T.E., S.M., C.N.-C., M.L., S.M., K.W., T.J.W., W.H.L.K., E.B., V.G., B.M.P., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K.

Analysis and interpretations of data: K.L.L., N.L.G., A.P., M.M., J.B., D.E.A. and K.W.

Drafting of the manuscript: P.T.E., K.L.L., E.J.B., S.R.H. and S.K.

Critical revision of the manuscript for important intellectual content: K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., P.I.W.d.B., M.M., S.A.L., E.F., D.D., N.L.S., J.D.S., R.B.S., E.Z.S., K.M.R., D.R.V.W., B.-M.B., C.v.N., K.W., G.B.E., S.L.H., G.S., A.V.S., L.J.L., T.B.H., S.M., M.M.N., D.J.M., S.P., T.E., A.K., S.M., C.N.-C., M.L., S.M.,T.J.W., W.H.L.K., R.S.V., M.N., C.A.M., B.H.C.S., A.H., A.G.U., D.L., E.B., A.M., E.J.T., A.C., V.G., B.M.P., D.M.R., T.M., H.-E.W., J.C.M.W., J.B., D.E.A., E.J.B. and S.R.H.

Statistical analysis: K.L.L., N.L.G., A.P., M.M., J.B., D.E.A. and K.W.

Obtained funding: P.T.E., A.P., A.A., M.K.C., M.F.S., P.I.W.d.B., M.M., S.A.L., E.F., N.L.S., J.D.S., K.M.R., D.R.V.W., J.I.R., S.L.H., S.M., B.H.Ch.S., A.H., A.G.U., D.L., E.B., A.M., E.J.T., A.C., V.G., B.M.P., D.M.R., T.M., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K.

Study supervision: P.T.E., K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K.

P.T.E., K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Competing interests

A.C. 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 Patrick T Ellinor or Stefan Kääb.

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https://doi.org/10.1038/ng.537

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