Genetic insight into sick sinus syndrome
- Creators
- Thorolfsdottir, Rosa B.
- Sveinbjornsson, Gardar
- Aegisdottir, Hildur M.
- Benonisdottir, Stefania
- Stefansdottir, Lilja
- Ivarsdottir, Erna V.
- Halldorsson, Gisli H.
- Sigurdsson, Jon K.
- Torp-Pedersen, Christian
- Weeke, Peter E.
- Brunak, Søren
- Westergaard, David
- Pedersen, Ole B.
- Sorensen, Erik
- Nielsen, Kaspar R.
- Burgdorf, Kristoffer S.
- Banasik, Karina
- Brumpton, Ben
- Zhou, Wei
- Oddsson, Asmundur
- Tragante, Vinicius
- Hjorleifsson, Kristjan E.
- Davidsson, Olafur B.
- Rajamani, Sridharan
- Jonsson, Stefan
- Torfason, Bjarni
- Valgardsson, Atli S.
- Thorgeirsson, Gudmundur
- Frigge, Michael L.
- Thorleifsson, Gudmar
- Norddahl, Gudmundur L.
- Helgadottir, Anna
- Gretarsdottir, Solveig
- Sulem, Patrick
- Jonsdottir, Ingileif
- Willer, Cristen J.
- Hveem, Kristian
- Bundgaard, Henning
- Ullum, Henrik
- Arnar, David O.
- Thorsteinsdottir, Unnur
- Gudbjartsson, Daniel F.
- Holm, Hilma
- Stefansson, Kari
- DBDS Genomic Consortium
Abstract
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.
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 (http://creativecommons.org/licenses/by-nc/4.0/), 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 http://www.decode.com/summarydata.Attached Files
Published - ehaa1108.pdf
Supplemental Material - ehaa1108_supplementary_data.zip
Files
Name | Size | Download all |
---|---|---|
md5:e9327c7865cc4c9d4d0d9728b9d58c92
|
2.0 MB | Preview Download |
md5:081b602de018624a202868555cd0f403
|
5.5 MB | Preview Download |
Additional details
- PMCID
- PMC8140484
- Eprint ID
- 108071
- Resolver ID
- CaltechAUTHORS:20210216-140504172
- 90580
- NordForsk
- 8114-00033B
- Innovation Fund Denmark
- 90580
- Technology Development Fund (Iceland)
- Created
-
2021-02-19Created from EPrint's datestamp field
- Updated
-
2021-05-28Created from EPrint's last_modified field