Letter | Published:

Genome-wide association study of PR interval

Nature Genetics volume 42, pages 153159 (2010) | Download Citation

Abstract

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 × 10−8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

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Acknowledgements

We gratefully acknowledge all of the participants in the studies. AGES: US National Institutes of Health (NIH) N01-AG-12100, US National Institute on Aging (NIA) and NIH Intramural Research Programs, Hjartavernd (Icelandic Heart Association), Althingi (Icelandic parliament), US National Heart, Lung, and Blood Institute (NHLBI), US National Eye Institute and US National Institute on Deafness and Other Communication Disorders. ARIC: NHLBI N01-HC-55015, N01-HC-55016, N01-HC-55018 through N01-HC-55022, R01-HL-087641, R01-HL-59367, R01-HL-086694 and R01-HL-054512; US National Human Genome Research Institute (NHGRI) U01-HG004402; NIH HHSN268200625226C; and the Donald W. Reynolds Cardiovascular Clinical Research Center. Infrastructure was supported by NIH UL1-RR025005. CCAF: NHLBI R01-HL090620 and P50-HL077107, and intramural funding from the Heart and Vascular Institute, Department of Cardiovascular Medicine, Cleveland Clinic. CHS: NHLBI N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, U01-HL-080295, R01-HL-087652 and R01-HL-088456; US National Center for Research Resources M01-RR-00425; National Institute of Diabetes and Digestive and Kidney Diseases DK063491; US National Institute of Neurological Disorders and Stroke; and the Cedars-Sinai Board of Governors. FHS: NIH N01-HC-25195, HL-076784, AG-028321, N01-HC25195, HL-080025 and 6R01-NS-17950; NHLBI N01-HC-25195; Boston University School of Medicine and Boston Medical Center (LINGA-II); the Robert Dawson Evans Endowment; the Doris Duke Charitable Foundation; the SHARe project; Deutsche Forschungsgemeinschaft fellowship SCHN 1149/1-1; Affymetrix contract for genotyping services (N02-HL-6-4278); and Pfizer. KORA/AFNET: We thank B. Pütz, M. Putz and G. Fischer for their contributions to genotyping and imputation. Bundesministerium für Bildung und Forschung Nationales Genomforschungsnetz; 01-GS-0499, 01-GR-0103, 01-GR-0803, AFNET 01-GI-0204 01-GS-0838, the Leducq Foundation 07-CVD 03, Ludwig-Maximilians University (LMU) FöFoLe 557/569, the LMU Excellence Initiative, MC Health as part of LMUinnovativ, the Helmholtz Zentrum München für Gesundheit und Umwelt and the state of Bavaria. Rotterdam Study: We thank P. Arp, M. Jhamai, M. Moorhouse, M. Verkerk and S. Bervoets for their help in creating the database, K. Estrada for his help with the analyses and M. Struchalin for contributions to genotype imputation. Nederlandse Organisatie voor Wetenschappelijk Onderzoek (The Netherlands Organisation for Scientific Research) 175.010.2005.011, 911.03.012 and 050-060-810, the Research Institute of Diseases in the Elderly, Netherlands Genome Initiative, Stichting Zorgonderzoek Nederland-Medische Wetenschappen (The Netherlands Organisation for Health Research and Development), Netherlands Hartstichting, Netherlands Ministry of Education Culture and Science, Netherlands Ministry of Health Welfare and Sports; the European Commission; Erasmus Medical Center, Erasmus University Rotterdam and the municipality of Rotterdam. SardiNIA: We thank A. Scuteri and M. Orrù for longstanding, continual support of the project and for phenotype characterization. NIA NO1-AG-1-2109, 263-MA-410953, NIH and NIA Intramural Research Programs, NHGRI and NHLBI. Role of the sponsors: None of the funding organizations had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review or approval of the manuscript. More detailed acknowledgments can be found in the Supplementary Note.

Author information

Author notes

    • Arne Pfeufer
    • , Charlotte van Noord
    • , Kristin D Marciante
    • , Dan E Arking
    • , Martin G Larson
    • , Albert Vernon Smith
    • , Kirill V Tarasov
    • , Vilmundur Gudnason
    • , Patrick T Ellinor
    • , Serena Sanna
    • , Stefan Kääb
    • , Jacqueline C M Witteman
    • , Alvaro Alonso
    • , Emelia J Benjamin
    •  & Susan R Heckbert

    These authors contributed equally to this work.

Affiliations

  1. Institute of Human Genetics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.

    • Arne Pfeufer
    •  & Thomas Meitinger
  2. Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Arne Pfeufer
    •  & Thomas Meitinger
  3. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Charlotte van Noord
    • , Germaine C Verwoert
    • , Fernando Rivadeneira
    • , Albert Hofman
    • , Bruno H C Stricker
    • , André G Uitterlinden
    • , Cornelia M van Duijn
    •  & Jacqueline C M Witteman
  4. Dutch Medicines Evaluation Board, The Hague, The Netherlands.

    • Charlotte van Noord
  5. Netherlands Consortium on Healthy Aging (NCHA) Leiden, The Netherlands.

    • Charlotte van Noord
    •  & Jacqueline C M Witteman
  6. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Kristin D Marciante
    • , Joshua C Bis
    •  & Bruce M Psaty
  7. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

    • Dan E Arking
    • , Georg B Ehret
    •  & Aravinda Chakravarti
  8. Department of Mathematics and Statistics, Boston University, Boston, Massachusetts, USA.

    • Martin G Larson
  9. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Martin G Larson
    • , Thomas J Wang
    • , Renate B Schnabel
    • , Ramachandran S Vasan
    • , Daniel Levy
    •  & Emelia J Benjamin
  10. Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Kopavogur, Iceland.

    • Albert Vernon Smith
    • , Thor Aspelund
    • , Gudny Eiriksdottir
    •  & Vilmundur Gudnason
  11. Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, Maryland, USA.

    • Kirill V Tarasov
    • , Samer S Najjar
    •  & Edward Lakatta
  12. Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA.

    • Kirill V Tarasov
    •  & David Schlessinger
  13. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Martina Müller
    • , Wiebke Sauter
    • , Christian Gieger
    •  & H-Erich Wichmann
  14. Department of Medicine I, Klinikum Grosshadern, Munich, Germany.

    • Martina Müller
    • , Moritz F Sinner
    • , Britt M Beckmann
    •  & Stefan Kääb
  15. Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Nona Sotoodehnia
  16. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Germaine C Verwoert
    • , Fernando Rivadeneira
    • , Bruno H C Stricker
    •  & André G Uitterlinden
  17. Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Man Li
    • , W H Linda Kao
    • , Anna Köttgen
    •  & Josef Coresh
  18. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

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

    • Bruce M Psaty
  20. Group Health Research Institute, Seattle, Washington, USA.

    • Bruce M Psaty
    •  & Susan R Heckbert
  21. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Kenneth Rice
  22. Medical Genetics Institute, Department of Common Diseases Genetics Program, Cedars-Sinai Medical Center, West Hollywood, California, USA.

    • Jerome I Rotter
  23. Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Jan A Kors
  24. Inspectorate for Health Care, The Hague, The Netherlands.

    • Bruno H C Stricker
  25. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

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

    • Steven A Lubitz
    • , Christopher Newton-Cheh
    • , Thomas J Wang
    •  & Patrick T Ellinor
  27. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Christopher Newton-Cheh
    •  & Patrick T Ellinor
  28. Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Christopher Newton-Cheh
    • , Thomas J Wang
    •  & Patrick T Ellinor
  29. Boston University School of Medicine, Boston, Massachusetts, USA.

    • Jared W Magnani
    •  & Ramachandran S Vasan
  30. Gutenberg Heart Study, Medical Clinic II (Cardiology), Johannes Gutenberg-University, Mainz, Germany.

    • Renate B Schnabel
  31. Heart & Vascular and Lerner Research Institutes, Cleveland Clinic, Cleveland, Ohio, USA.

    • Mina K Chung
    • , John Barnard
    • , Jonathan D Smith
    •  & David R Van Wagoner
  32. Heart Preventive Clinical and Research Institute, University of Iceland, Reykjavik, Iceland.

    • Thor Aspelund
    •  & Vilmundur Gudnason
  33. Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Baltimore, Maryland, USA.

    • Tamara B Harris
    •  & Lenore J Launer
  34. Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy.

    • Manuela Uda
    •  & Serena Sanna
  35. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

    • Gonçalo R Abecasis
  36. Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany.

    • Bertram Müller-Myhsok
  37. Human Genetics Center and Institute for Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA.

    • Eric Boerwinkle
  38. Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

    • Aravinda Chakravarti
  39. Epidemiological Cardiology Research Center (EPICARE), Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University Medical Center, Winston-Salem, North Carolina, USA.

    • Elsayed Z Soliman
  40. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Kathryn L Lunetta
  41. Institute of Biological and Medical Imaging, Helmholtz Center, Munich, Germany.

    • Siegfried Perz
  42. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • H-Erich Wichmann
  43. Klinikum Grosshadern, Munich, Germany.

    • H-Erich Wichmann
  44. Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

    • Daniel Levy
  45. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

    • Alvaro Alonso
  46. Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USA.

    • Emelia J Benjamin
  47. Cardiology and Preventive Medicine Division, Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Emelia J Benjamin

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Contributions

Study concept and design: A.P., D.E.A., A.V.S., N.S., J.I.R., A.H., B.H.C.S., C.M.v.D., G.E., A.C., K.L.L., V.G., P.T.E., S.S., S.K., J.C.M.W., E.J.B., S.R.H. Acquisition of data: A.P., C.v.N., D.E.A., K.V.T., M.F.S., J.I.R., F.R., J.A.K., B.H.C.S., A.G.U., B.M.B., W.S., C.G., C.N.-C., T.J.W., M.K.C., J.D.S., D.R.V.W., S.S.N., G.B.E., A.C., E.Z.S., S.P., J.C.M.W., A.A., S.R.H. Analysis and interpretation of data: A.P., C.v.N., K.D.M., D.E.A., A.V.S., M.M., N.S., G.C.V., M.L., J.I.R., C.N.-C., T.J.W., R.S.V., T.A., S.S.N., G.B.E., A.C., E.Z.S., K.L.L., S.P., V.G., E.J.B., S.R.H. Drafting the manuscript: A.P., D.E.A., N.S., P.T.E., S.K., E.J.B., S.R.H. Critical revision of the manuscript: C.v.N., K.D.M., M.G.L., A.V.S., K.V.T., M.M., M.F.S., G.C.V., W.H.L.K., A.K., J.C., J.C.B., B.M.P., K.R., J.I.R., F.R., A.H., J.A.K., B.H.C.S., A.G.U., C.M.v.D., B.M.B., C.G., S.A.L., C.N.-C., T.J.W., J.W.M., R.B.S., M.K.C., J.B., J.D.S., D.R.V.W., R.S.V., G.E., L.J.L., T.B.H., E.L., D.S., M.U., G.R.A., B.M.-M., E.B., E.Z.S., K.L.L., H.-E.W., T.M., D.L., V.G., S.S., J.C.M.W., A.A. Statistical analysis: A.P., C.v.N., D.E.A., M.G.L., A.V.S., M.M., G.C.V., M.L., W.H.L.K., J.C.B., K.R., T.A., K.L.L. Obtaining funding: A.P., M.F.S., B.M.P., J.I.R., F.R., A.H., A.G.U., M.K.C., J.D.S., R.S.V., G.E., D.S., M.U., G.R.A., E.B., A.C., H.-E.W., T.M., D.L., V.G., J.C.M.W., S.R.H. Study supervision: J.I.R., F.R., A.H., B.H.C.S., A.G.U., C.M.v.D., G.E., A.C., V.G., J.C.M.W., S.R.H. The following authors had full data access and take responsibility for analysis: A.P., C.v.N., M.M., J.I.R., A.C., K.L.L, S.R.H. Cohort study investigators: a list of investigators by cohort study may be found in the Supplementary Note.

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 Arne Pfeufer or Susan R Heckbert.

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https://doi.org/10.1038/ng.517

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