Genetic insight into sick sinus syndrome

Rosa B Thorolfsdottir¹, Gardar Sveinbjornsson¹, Hildur M Aegisdottir¹, Stefania Benonisdottir¹, Lilja Stefansdottir¹, Erna V Ivarsdottir¹, Gisli H Halldorsson¹, Jon K Sigurdsson¹, Christian Torp-Pedersen², Peter E Weeke³, Søren Brunak⁴, David Westergaard⁴, Ole B Pedersen⁵, Erik Sorensen⁶, Kaspar R Nielsen⁷, Kristoffer S Burgdorf⁶, Karina Banasik⁴, Ben Brumpton⁸, Wei Zhou⁹, Asmundur Oddsson¹, Vinicius Tragante¹, Kristjan E Hjorleifsson^{1

10}, Olafur B Davidsson¹, Sridharan Rajamani¹, Stefan Jonsson¹, Bjarni Torfason^{11

12}, Atli S Valgardsson¹², Gudmundur Thorgeirsson^{1

11

13}, Michael L Frigge¹, Gudmar Thorleifsson¹, Gudmundur L Norddahl¹, Anna Helgadottir¹, Solveig Gretarsdottir¹, Patrick Sulem¹, Ingileif Jonsdottir^{1

11

14}, Cristen J Willer^{9

15

16}, Kristian Hveem^{17

18

19}, Henning Bundgaard³, Henrik Ullum^{6

20}, David O Arnar^{1

11

13}, Unnur Thorsteinsdottir^{1

11}, Daniel F Gudbjartsson^{1

21}, Hilma Holm¹, Kari Stefansson^{1

11}; DBDS Genomic Consortium

Collaborators, Affiliations

Collaborators

DBDS Genomic Consortium:
Steffen Andersen, Christian Erikstrup, Thomas F Hansen, Henrik Hjalgrim, Gregor Jemec, Poul Jennum, Mette Nyegaard, Mie T Bruun, Mikkel Petersen, Thomas Werge, Per I Johansson

Affiliations

¹ deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 101, Iceland.
² Department of Clinical Research and Cardiology, Nordsjaelland Hospital, Dyrehavevej 29, Hillerød 3400, Denmark.
³ Department of Cardiology, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen 2100, Denmark.
⁴ Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3A, Copenhagen 2200, Denmark.
⁵ Department of Clinical Immunology, Naestved Hospital, Ringstedgade 77B, Naestved 4700, Denmark.
⁶ Department of Clinical Immunology, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen 2100, Denmark.
⁷ Department of Clinical Immunology, Aalborg University Hospital North, Urbansgade 36, Aalborg 9000, Denmark.
⁸ Department of Thoracic and Occupational Medicine, St. Olavs Hospital, Trondheim University Hospital, Prinsesse Kristinas gate 3, Trondheim 7030, Norway.
⁹ Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, MI 48109-2218, USA.
¹⁰ Department of Computing and Mathematical Sciences, California Institute of Technology, 1200 E California Blvd. MC 305-16, Pasadena, CA 91125, USA.
¹¹ Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik 101, Iceland.
¹² Department of Cardiothoracic Surgery, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland.
¹³ Department of Medicine, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland.
¹⁴ Department of Immunology, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland.
¹⁵ Department of Internal Medicine: Cardiology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109 -5368, USA.
¹⁶ Department of Human Genetics, University of Michigan, 4909 Buhl Building, 1241 E. Catherine St., Ann Arbor, MI 48109 -5618, USA.
¹⁷ K.G. Jebsen Center for Genetic Epidemiology, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Erling Skjalgssons gt. 1, Trondheim 7491, Norway.
¹⁸ Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Postboks 8905, Trondheim 7491, Norway.
¹⁹ HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Forskningsveien 2, Levanger 7600, Norway.
²⁰ Statens Serum Institut, Artillerivej 5, Copenhagen 2300, Denmark.
²¹ School of Engineering and Natural Sciences, University of Iceland, Hjardarhagi 4, Reykjavik 107, Iceland.

PMID: 36282123
DOI: 10.1093/eurheartj/ehaa1108

Genetic insight into sick sinus syndrome

Rosa B Thorolfsdottir et al. Eur Heart J. 2021.

. 2021 May 21;42(20):1959-1971.

doi: 10.1093/eurheartj/ehaa1108.

Authors

Collaborators

DBDS Genomic Consortium:
Steffen Andersen, Christian Erikstrup, Thomas F Hansen, Henrik Hjalgrim, Gregor Jemec, Poul Jennum, Mette Nyegaard, Mie T Bruun, Mikkel Petersen, Thomas Werge, Per I Johansson

Affiliations

¹ deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 101, Iceland.
² Department of Clinical Research and Cardiology, Nordsjaelland Hospital, Dyrehavevej 29, Hillerød 3400, Denmark.
³ Department of Cardiology, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen 2100, Denmark.
⁴ Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3A, Copenhagen 2200, Denmark.
⁵ Department of Clinical Immunology, Naestved Hospital, Ringstedgade 77B, Naestved 4700, Denmark.
⁶ Department of Clinical Immunology, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen 2100, Denmark.
⁷ Department of Clinical Immunology, Aalborg University Hospital North, Urbansgade 36, Aalborg 9000, Denmark.
⁸ Department of Thoracic and Occupational Medicine, St. Olavs Hospital, Trondheim University Hospital, Prinsesse Kristinas gate 3, Trondheim 7030, Norway.
⁹ Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, MI 48109-2218, USA.
¹⁰ Department of Computing and Mathematical Sciences, California Institute of Technology, 1200 E California Blvd. MC 305-16, Pasadena, CA 91125, USA.
¹¹ Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik 101, Iceland.
¹² Department of Cardiothoracic Surgery, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland.
¹³ Department of Medicine, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland.
¹⁴ Department of Immunology, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland.
¹⁵ Department of Internal Medicine: Cardiology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109 -5368, USA.
¹⁶ Department of Human Genetics, University of Michigan, 4909 Buhl Building, 1241 E. Catherine St., Ann Arbor, MI 48109 -5618, USA.
¹⁷ K.G. Jebsen Center for Genetic Epidemiology, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Erling Skjalgssons gt. 1, Trondheim 7491, Norway.
¹⁸ Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Postboks 8905, Trondheim 7491, Norway.
¹⁹ HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Forskningsveien 2, Levanger 7600, Norway.
²⁰ Statens Serum Institut, Artillerivej 5, Copenhagen 2300, Denmark.
²¹ School of Engineering and Natural Sciences, University of Iceland, Hjardarhagi 4, Reykjavik 107, Iceland.

PMID: 36282123
DOI: 10.1093/eurheartj/ehaa1108

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.

Keywords: KRT8; Atrial fibrillation; GWAS; Mendelian randomization; Sick sinus syndrome.

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Genetic insight into sick sinus syndrome

Collaborators

Affiliations

Genetic insight into sick sinus syndrome

Authors

Collaborators

Affiliations

Abstract

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Full Text Sources

Medical

Research Materials

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