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A rare variant in MYH6 is associated with high risk of sick sinus syndrome

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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Figure 1: Study design and outcomes.
Figure 2: An overview of the region around c.2161C>T.
Figure 3: Penetrance of sick sinus syndrome among carriers and non-carriers of c.2161C>T.

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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.

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Authors and Affiliations

Authors

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.

Corresponding authors

Correspondence to Hilma Holm or Kari Stefansson.

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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.

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Supplementary Tables 1–8 and Supplementary Figures 1–4. (PDF 1162 kb)

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Holm, H., Gudbjartsson, D., Sulem, P. et al. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat Genet 43, 316–320 (2011). https://doi.org/10.1038/ng.781

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