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

Hilma Holm; Daniel F Gudbjartsson; Patrick Sulem; Gisli Masson; Hafdis Th Helgadottir; Carlo Zanon; Olafur Th Magnusson; Agnar Helgason; Jona Saemundsdottir; Arnaldur Gylfason; Hrafnhildur Stefansdottir; Solveig Gretarsdottir; Stefan E Matthiasson; Gu Mundur Thorgeirsson; Aslaug Jonasdottir; Asgeir Sigurdsson; Hreinn Stefansson; Thomas Werge; Thorunn Rafnar; Lambertus A Kiemeney; Babar Parvez; Raafia Muhammad; Dan M Roden; Dawood Darbar; Gudmar Thorleifsson; G Bragi Walters; Augustine Kong; Unnur Thorsteinsdottir; David O Arnar; Kari Stefansson

doi:10.1038/ng.781

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

Hilma Holm, Daniel F Gudbjartsson, Patrick Sulem, Gisli Masson, Hafdis Th Helgadottir, Carlo Zanon, Olafur Th Magnusson, Agnar Helgason, Jona Saemundsdottir, Arnaldur Gylfason, Hrafnhildur Stefansdottir, Solveig Gretarsdottir, Stefan E Matthiasson, Gu Mundur Thorgeirsson, Aslaug Jonasdottir, Asgeir Sigurdsson, Hreinn Stefansson, Thomas Werge, Thorunn Rafnar, Lambertus A KiemeneyBabar Parvez, Raafia Muhammad, Dan M Roden, Dawood Darbar, Gudmar Thorleifsson, G Bragi Walters, Augustine Kong, Unnur Thorsteinsdottir, David O Arnar, Kari Stefansson

202 Citations (Scopus)

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.

Original language	English
Journal	Nature Genetics
Volume	43
Issue number	4
Pages (from-to)	316-20
Number of pages	5
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.781 https://doi.org/10.1038/ng.781
Publication status	Published - Feb 2011

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Holm, H., Gudbjartsson, D. F., Sulem, P., Masson, G., Helgadottir, H. T., Zanon, C., Magnusson, O. T., Helgason, A., Saemundsdottir, J., Gylfason, A., Stefansdottir, H., Gretarsdottir, S., Matthiasson, S. E., Thorgeirsson, G. M., Jonasdottir, A., Sigurdsson, A., Stefansson, H., Werge, T., Rafnar, T., ... Stefansson, K. (2011). A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nature Genetics, 43(4), 316-20. https://doi.org/10.1038/ng.781, https://doi.org/10.1038/ng.781

Holm, H, Gudbjartsson, DF, Sulem, P, Masson, G, Helgadottir, HT, Zanon, C, Magnusson, OT, Helgason, A, Saemundsdottir, J, Gylfason, A, Stefansdottir, H, Gretarsdottir, S, Matthiasson, SE, Thorgeirsson, GM, Jonasdottir, A, Sigurdsson, A, Stefansson, H, Werge, T, Rafnar, T, Kiemeney, LA, Parvez, B, Muhammad, R, Roden, DM, Darbar, D, Thorleifsson, G, Walters, GB, Kong, A, Thorsteinsdottir, U, Arnar, DO & Stefansson, K 2011, 'A rare variant in MYH6 is associated with high risk of sick sinus syndrome', Nature Genetics, vol. 43, no. 4, pp. 316-20. https://doi.org/10.1038/ng.781, https://doi.org/10.1038/ng.781

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title = "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.",

author = "Hilma Holm and Gudbjartsson, {Daniel F} and Patrick Sulem and Gisli Masson and Helgadottir, {Hafdis Th} and Carlo Zanon and Magnusson, {Olafur Th} and Agnar Helgason and Jona Saemundsdottir and Arnaldur Gylfason and Hrafnhildur Stefansdottir and Solveig Gretarsdottir and Matthiasson, {Stefan E} and Thorgeirsson, {Gu Mundur} and Aslaug Jonasdottir and Asgeir Sigurdsson and Hreinn Stefansson and Thomas Werge and Thorunn Rafnar and Kiemeney, {Lambertus A} and Babar Parvez and Raafia Muhammad and Roden, {Dan M} and Dawood Darbar and Gudmar Thorleifsson and Walters, {G Bragi} and Augustine Kong and Unnur Thorsteinsdottir and Arnar, {David O} and Kari Stefansson",

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doi = "10.1038/ng.781",

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AU - Holm, Hilma

AU - Gudbjartsson, Daniel F

AU - Sulem, Patrick

AU - Masson, Gisli

AU - Helgadottir, Hafdis Th

AU - Zanon, Carlo

AU - Magnusson, Olafur Th

AU - Helgason, Agnar

AU - Saemundsdottir, Jona

AU - Gylfason, Arnaldur

AU - Stefansdottir, Hrafnhildur

AU - Gretarsdottir, Solveig

AU - Matthiasson, Stefan E

AU - Thorgeirsson, Gu Mundur

AU - Jonasdottir, Aslaug

AU - Sigurdsson, Asgeir

AU - Stefansson, Hreinn

AU - Werge, Thomas

AU - Rafnar, Thorunn

AU - Kiemeney, Lambertus A

AU - Parvez, Babar

AU - Muhammad, Raafia

AU - Roden, Dan M

AU - Darbar, Dawood

AU - Thorleifsson, Gudmar

AU - Walters, G Bragi

AU - Kong, Augustine

AU - Thorsteinsdottir, Unnur

AU - Arnar, David O

AU - Stefansson, Kari

PY - 2011/2

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N2 - 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.

AB - 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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DO - 10.1038/ng.781

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JO - Nature: New biology

JF - Nature: New biology

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

Abstract

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