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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References
Ferrer, M.I. The sick sinus syndrome in atrial disease. J. Am. Med. Assoc. 206, 645–646 (1968).
Saksena, S. & Camm, J.A. Electrophysiological Disorders of the Heart (Elsevier Churchill Livingstone, Philadelphia, 2004).
Epstein, A.E. et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J. Am. Coll. Cardiol. 51, e1–e62 (2008).
Kusumoto, F.M. & Goldschlager, N. Cardiac pacing. N. Engl. J. Med. 334, 89–99 (1996).
Benson, D.W. et al. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J. Clin. Invest. 112, 1019–1028 (2003).
Veldkamp, M.W. et al. Contribution of sodium channel mutations to bradycardia and sinus node dysfunction in a patient with sinus node disease in LQT3 families. Circ. Res. 92, 976–983 (2003).
Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T. & DiFrancesco, D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N. Engl. J. Med. 354, 151–157 (2006).
Mohler, P.J. et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 421, 634–639 (2003).
Dobrzynski, H., Boyett, M.R. & Anderson, R.H. New insights into pacemaker activity: promoting understanding of sick sinus syndrome. Circulation 115, 1921–1932 (2007).
International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).
Durbin, R.M. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).
Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).
Kong, A. et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat. Genet. 40, 1068–1075 (2008).
Thorlacius, S. et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat. Genet. 13, 117–119 (1996).
Slatkin, M. & Rannala, B. Estimating allele age. Annu. Rev. Genomics Hum. Genet. 1, 225–249 (2000).
Labuda, M. et al. Linkage disequilibrium analysis in young populations: pseudo-vitamin D-deficiency rickets and the founder effect in French Canadians. Am. J. Hum. Genet. 59, 633–643 (1996).
Holm, H. et al. Several common variants modulate heart rate, PR interval and QRS duration. Nat. Genet. 42, 117–122 (2010).
Eijgelsheim, M. et al. Genome-wide association analysis identifies multiple loci related to resting heart rate. Hum. Mol. Genet. 19, 3885–3894 (2010).
Fuster, V. et al. Hurst's The Heart (McGraw Hill, New York, New York, USA, 2004).
Epp, T.A., Dixon, I.M., Wang, H.Y., Sole, M.J. & Liew, C.C. Structural organization of the human cardiac alpha-myosin heavy chain gene (MYH6). Genomics 18, 505–509 (1993).
Franco, D., Lamers, W.H. & Moorman, A.F. Patterns of expression in the developing myocardium: towards a morphologically integrated transcriptional model. Cardiovasc. Res. 38, 25–53 (1998).
Mahdavi, V., Chambers, A.P. & Nadal-Ginard, B. Cardiac alpha- and beta-myosin heavy chain genes are organized in tandem. Proc. Natl. Acad. Sci. USA 81, 2626–2630 (1984).
Miyata, S., Minobe, W., Bristow, M.R. & Leinwand, L.A. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ. Res. 86, 386–390 (2000).
Carniel, E. et al. Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy. Circulation 112, 54–59 (2005).
Granados-Riveron, J.T. et al. Alpha-cardiac myosin heavy chain (MYH6) mutations affecting myofibril formation are associated with congenital heart defects. Hum. Mol. Genet. 19, 4007–4016 (2010).
Sweeney, H.L. & Houdusse, A. Myosin VI rewrites the rules for myosin motors. Cell 141, 573–582 (2010).
Sunyaev, S. et al. Prediction of deleterious human alleles. Hum. Mol. Genet. 10, 591–597 (2001).
Simon, A.M., Sutherland, L.B. & Paul, D.L. Control of stress-dependent cardiac growth and bundle branch block. Science 8, 575–579 (2007).
van Rooij, E. et al. A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance. Dev. Cell 17, 662–673 (2009).
Duan, J. et al. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum. Mol. Genet. 12, 205–216 (2003).
Wang, D., Johnson, A.D., Papp, A.C., Kroetz, D.L. & Sadee, W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet. Genomics 15, 693–704 (2005).
Zhang, H. et al. Association between two mu-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence. Hum. Mol. Genet. 15, 807–819 (2006).
Johansen, C.T. et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat. Genet. 42, 684–687 (2010).
Preuss, M. et al. Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study: a genome-wide association meta-analysis involving more than 22,000 cases and 60,000 controls. Circ. Cardiovasc. Genet. 3, 475–483 (2010).
Stefansson, H. et al. Common variants conferring risk of schizophrenia. Nature 460, 744–747 (2009).
Kiemeney, L.A. et al. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat. Genet. 40, 1307–1312 (2008).
Gudbjartsson, D.F. et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat. Genet. 41, 876–878 (2009).
Kutyavin, I.V. et al. A novel endonuclease IV post-PCR genotyping system. Nucleic Acids Res. 34, e128 (2006).
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).
Kong, A. et al. Fine-scale recombination rate differences between sexes, populations and individuals. Nature 467, 1099–1103 (2010).
Palsdottir, A. et al. A drastic reduction in the life span of cystatin C L68Q carriers due to life-style changes during the last two centuries. PLoS Genet 4, e1000099 (2008).
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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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.
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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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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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DOI: https://doi.org/10.1038/ng.781
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