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Genetic insight into sick sinus syndrome

Thorolfsdottir, Rosa B. and Sveinbjornsson, Gardar and Aegisdottir, Hildur M. and Benonisdottir, Stefania and Stefansdottir, Lilja and Ivarsdottir, Erna V. and Halldorsson, Gisli H. and Sigurdsson, Jon K. and Torp-Pedersen, Christian and Weeke, Peter E. and Brunak, Søren and Westergaard, David and Pedersen, Ole B. and Sorensen, Erik and Nielsen, Kaspar R. and Burgdorf, Kristoffer S. and Banasik, Karina and Brumpton, Ben and Zhou, Wei and Oddsson, Asmundur and Tragante, Vinicius and Hjorleifsson, Kristjan E. and Davidsson, Olafur B. and Rajamani, Sridharan and Jonsson, Stefan and Torfason, Bjarni and Valgardsson, Atli S. and Thorgeirsson, Gudmundur and Frigge, Michael L. and Thorleifsson, Gudmar and Norddahl, Gudmundur L. and Helgadottir, Anna and Gretarsdottir, Solveig and Sulem, Patrick and Jonsdottir, Ingileif and Willer, Cristen J. and Hveem, Kristian and Bundgaard, Henning and Ullum, Henrik and Arnar, David O. and Thorsteinsdottir, Unnur and Gudbjartsson, Daniel F. and Holm, Hilma and Stefansson, Kari (2021) Genetic insight into sick sinus syndrome. European Heart Journal, 42 (20). pp. 1959-1971. ISSN 0195-668X. PMCID PMC8140484. doi:10.1093/eurheartj/ehaa1108.

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Aims. The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results. We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1–1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10⁻²⁰), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion. We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle ItemGenome-wide association scan summary data
Thorolfsdottir, Rosa B.0000-0001-7475-0398
Sveinbjornsson, Gardar0000-0003-2429-9468
Ivarsdottir, Erna V.0000-0002-2069-0681
Halldorsson, Gisli H.0000-0001-7067-9862
Nielsen, Kaspar R.0000-0003-4406-9643
Burgdorf, Kristoffer S.0000-0002-7851-1818
Thorgeirsson, Gudmundur0000-0003-4623-9087
Sulem, Patrick0000-0001-7123-6123
Jonsdottir, Ingileif0000-0001-8339-150X
Willer, Cristen J.0000-0001-5645-4966
Ullum, Henrik0000-0001-7306-9058
Thorsteinsdottir, Unnur0000-0002-7049-2827
Gudbjartsson, Daniel F.0000-0002-5222-9857
Holm, Hilma0000-0002-9517-6636
Stefansson, Kari0000-0003-1676-864X
Additional Information:© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 28 April 2020; Revision received: 24 August 2020; Editorial decision: 21 December 2020; Accepted: 05 January 2021; Published: 13 February 2021. We thank all the study subjects for their valuable participation as well as our colleagues that contributed to data collection, sample handling, and genotyping. This work was partly supported by NordForsk through the funding to PM Heart, project number 90580, the Innovation Fund Denmark (IFD) under File No. 8114-00033B and the Technology Development Fund, Iceland, project number 90580. Conflict of interest: The following authors affiliated with deCODE genetics/Amgen, Inc., are employed by the company: R.B.T., G.S., H.M.A., S.B., L.S., E.V.I., G.H.H., J.K.S., A.O., V.T., K.E.H., O.B.D., S.R., S.J., G.T., M.L.F., G.T., G.L.N., A.H., S.G., P.S., I.J., D.O.A., U.T., D.F.G., H.H., and K.S.. D.W. received grants from Novo Nordisk Foundation during the conduct of the study. S.B. is a board member for Proscion A/S and Intomics A/S. Rosa B. Thorolfsdottir and Gardar Sveinbjornsson contributed equally to this work. Data availability: The Icelandic population WGS data has been deposited at the European Variant Archive under accession code PRJEB15197. We declare that the data supporting the findings of this study are available within the article, its Supplementary material online and upon reasonable request. The genome-wide association scan summary data will be made available at
Funding AgencyGrant Number
Innovation Fund Denmark8114-00033B
Technology Development Fund (Iceland)90580
Issue or Number:20
PubMed Central ID:PMC8140484
Record Number:CaltechAUTHORS:20210216-140504172
Persistent URL:
Official Citation:Rosa B Thorolfsdottir, Gardar Sveinbjornsson, Hildur M Aegisdottir, Stefania Benonisdottir, Lilja Stefansdottir, Erna V Ivarsdottir, Gisli H Halldorsson, Jon K Sigurdsson, Christian Torp-Pedersen, Peter E Weeke, Søren Brunak, David Westergaard, Ole B Pedersen, Erik Sorensen, Kaspar R Nielsen, Kristoffer S Burgdorf, Karina Banasik, Ben Brumpton, Wei Zhou, Asmundur Oddsson, Vinicius Tragante, Kristjan E Hjorleifsson, Olafur B Davidsson, Sridharan Rajamani, Stefan Jonsson, Bjarni Torfason, Atli S Valgardsson, Gudmundur Thorgeirsson, Michael L Frigge, Gudmar Thorleifsson, Gudmundur L Norddahl, Anna Helgadottir, Solveig Gretarsdottir, Patrick Sulem, Ingileif Jonsdottir, Cristen J Willer, Kristian Hveem, Henning Bundgaard, Henrik Ullum, David O Arnar, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, Hilma Holm, Kari Stefansson, DBDS Genomic Consortium, Genetic insight into sick sinus syndrome, European Heart Journal, Volume 42, Issue 20, 21 May 2021, Pages 1959–1971,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108071
Deposited By: George Porter
Deposited On:19 Feb 2021 20:46
Last Modified:28 May 2021 15:36

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