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

• Published in: Nature genetics Vol. 43; no. 4; pp. 316 - 320
• Main Authors: Holm, Hilma, Gudbjartsson, Daniel F, Sulem, Patrick, Masson, Gisli, Helgadottir, Hafdis Th, Zanon, Carlo, Magnusson, Olafur Th, Helgason, Agnar, Saemundsdottir, Jona, Gylfason, Arnaldur, Stefansdottir, Hrafnhildur, Gretarsdottir, Solveig, Matthiasson, Stefan E, Thorgeirsson, Gu∂mundur, Jonasdottir, Aslaug, Sigurdsson, Asgeir, Stefansson, Hreinn, Werge, Thomas, Rafnar, Thorunn, Kiemeney, Lambertus A, Parvez, Babar, Muhammad, Raafia, Roden, Dan M, Darbar, Dawood, Thorleifsson, Gudmar, Walters, G Bragi, Kong, Augustine, Thorsteinsdottir, Unnur, Arnar, David O, Stefansson, Kari
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2011; Nature Publishing Group
• Subjects: 631/208/205/2138; 631/208/727/2000; 692/699/75/29; Adult; Aged; Aged, 80 and over; Agriculture; Amino acids; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cardiac arrhythmia; Cardiac dysrhythmias; Cardiac Myosins - genetics; Cardiology. Vascular system; Care and treatment; Case-Control Studies; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genomes; Heart; Heart Diseases - genetics; Heart Rate - genetics; Heterozygote; Human Genetics; Humans; Iceland; Male; Medical sciences; Middle Aged; Mutation; Mutation, Missense; Myosin Heavy Chains - genetics; Odds Ratio; Oligonucleotide Array Sequence Analysis; Penetrance; Polymorphism, Single Nucleotide; Risk factors; Sick sinus syndrome; Sick Sinus Syndrome - genetics; Sick Sinus Syndrome - physiopathology; Single nucleotide polymorphisms; Sinuses; Iceland; United States; Variant; High risk; Arrhythmia; Heart disease; Cardiovascular disease; Excitability disorder; Sick sinus syndrome
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.781

Hilma Holm et al . report a rare missense variant MYH6 that is associated with a high risk of sick sinus syndrome in Icelanders. This heart condition is found most often in elderly people and is the most frequent reason a heart pacemaker is implanted. 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.