Abstract

Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10−29. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.

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Acknowledgements

The authors would like to thank the individuals that participated in this study and made it possible. We also thank all our valued colleagues who contributed to this work. The Vanderbilt Atrial Fibrillation Registry is supported by US National Institutes of Health grants U19HL065962 and HL092217.

Author information

Author notes

    • Hilma Holm
    •  & Daniel F Gudbjartsson

    These authors contributed equally to this work.

Affiliations

  1. deCODE genetics, Sturlugata 8, Reykjavik, Iceland.

    • Hilma Holm
    • , Daniel F Gudbjartsson
    • , Patrick Sulem
    • , Gisli Masson
    • , Hafdis Th Helgadottir
    • , Carlo Zanon
    • , Olafur Th Magnusson
    • , Agnar Helgason
    • , Jona Saemundsdottir
    • , Arnaldur Gylfason
    • , Solveig Gretarsdottir
    • , Aslaug Jonasdottir
    • , Asgeir Sigurdsson
    • , Hreinn Stefansson
    • , Thorunn Rafnar
    • , Gudmar Thorleifsson
    • , G Bragi Walters
    • , Augustine Kong
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  2. Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland.

    • Hrafnhildur Stefansdottir
    • , Gu∂mundur Thorgeirsson
    •  & David O Arnar
  3. Laekning, Medical Clinics, Reykjavik, Iceland.

    • Stefan E Matthiasson
  4. University of Iceland, Faculty of Medicine, Reykjavik, Iceland.

    • Gu∂mundur Thorgeirsson
    • , Unnur Thorsteinsdottir
    • , David O Arnar
    •  & Kari Stefansson
  5. Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark.

    • Thomas Werge
  6. Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Lambertus A Kiemeney
  7. Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Lambertus A Kiemeney
  8. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Babar Parvez
    • , Raafia Muhammad
    • , Dan M Roden
    •  & Dawood Darbar

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Contributions

The study was designed and results interpreted by H. Holm, D.F.G., D.O.A., P.S., U.T. and K.S. O.M., J.S., A.J., A.S., G.B.W. and H. Helgadottir managed and contributed to sequencing and genotyping. Data alignment, imputation and statistical analysis was carried out by D.F.G., G.M., A.G., P.S., G. Thorleifsson and A.K. Additional analyses were performed by A.H. and C.Z. D.O.A., H. Holm, G. Thorgeirsson, S.E.M. and H. Stefansson collected the Icelandic data. Foreign data was collected and supervised by H. Stefansson, T.W., T.R., L.A.K., B.P., R.M., D.M.R. and D.D. H. Holm, D.F.G., D.O.A., U.T. and K.S. wrote the first draft of the paper. All authors contributed to the final version of the manuscript.

Competing interests

The authors that are affiliated with deCODE genetics are all employees of deCODE, a biotechnology company that provides genetic testing services, and some own stocks or stock options in the company.

Corresponding authors

Correspondence to Hilma Holm or Kari Stefansson.

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DOI

https://doi.org/10.1038/ng.781

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