Genetic insight into sick sinus syndrome
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Genetic insight into sick sinus syndrome. / 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.; Sørensen, 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.
I: European Heart Journal, Bind 42, 2021.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Genetic insight into sick sinus syndrome
AU - Thorolfsdottir, Rosa B
AU - Sveinbjornsson, Gardar
AU - Aegisdottir, Hildur M
AU - Benonisdottir, Stefania
AU - Stefansdottir, Lilja
AU - Ivarsdottir, Erna V
AU - Halldorsson, Gisli H
AU - Sigurdsson, Jon K
AU - Torp-Pedersen, Christian
AU - Weeke, Peter E
AU - Brunak, Søren
AU - Westergaard, David
AU - Pedersen, Ole B.
AU - Sørensen, Erik
AU - Nielsen, Kaspar R
AU - Burgdorf, Kristoffer S.
AU - Banasik, Karina
AU - Brumpton, Ben
AU - Zhou, Wei
AU - Oddsson, Asmundur
AU - Tragante, Vinicius
AU - Hjorleifsson, Kristjan E
AU - Davidsson, Olafur B
AU - Rajamani, Sridharan
AU - Jonsson, Stefan
AU - Torfason, Bjarni
AU - Valgardsson, Atli S
AU - Thorgeirsson, Gudmundur
AU - Frigge, Michael L
AU - Thorleifsson, Gudmar
AU - Norddahl, Gudmundur L
AU - Helgadottir, Anna
AU - Gretarsdottir, Solveig
AU - Sulem, Patrick
AU - Jonsdottir, Ingileif
AU - Willer, Cristen J
AU - Hveem, Kristian
AU - Bundgaard, Henning
AU - Ullum, Henrik
AU - Arnar, David O
AU - Thorsteinsdottir, Unnur
AU - Gudbjartsson, Daniel F
AU - Holm, Hilma
AU - Stefansson, Kari
AU - DBDS Genomic Consortium
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1093/eurheartj/ehaa1108
DO - 10.1093/eurheartj/ehaa1108
M3 - Journal article
C2 - 33580673
VL - 42
JO - European Heart Journal
JF - European Heart Journal
SN - 0195-668X
ER -
ID: 259833875