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Genetic insight into sick sinus syndrome

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Harvard

Thorolfsdottir, RB, Sveinbjornsson, G, Aegisdottir, HM, Benonisdottir, S, Stefansdottir, L, Ivarsdottir, EV, Halldorsson, GH, Sigurdsson, JK, Torp-Pedersen, C, Weeke, PE, Brunak, S, Westergaard, D, Pedersen, OB, Sorensen, E, Nielsen, KR, Burgdorf, KS, Banasik, K, Brumpton, B, Zhou, W, Oddsson, A, Tragante, V, Hjorleifsson, KE, Davidsson, OB, Rajamani, S, Jonsson, S, Torfason, B, Valgardsson, AS, Thorgeirsson, G, Frigge, ML, Thorleifsson, G, Norddahl, GL, Helgadottir, A, Gretarsdottir, S, Sulem, P, Jonsdottir, I, Willer, CJ, Hveem, K, Bundgaard, H, Ullum, H, Arnar, DO, Thorsteinsdottir, U, Gudbjartsson, DF, Holm, H, Stefansson, K & DBDS Genomic Consortium 2021, 'Genetic insight into sick sinus syndrome', European Heart Journal, vol. 42, no. 20, pp. 1959-1971. https://doi.org/10.1093/eurheartj/ehaa1108

APA

Thorolfsdottir, R. B., Sveinbjornsson, G., Aegisdottir, H. M., Benonisdottir, S., Stefansdottir, L., Ivarsdottir, E. V., Halldorsson, G. H., Sigurdsson, J. K., Torp-Pedersen, C., Weeke, P. E., Brunak, S., Westergaard, D., Pedersen, O. B., Sorensen, E., Nielsen, K. R., Burgdorf, K. S., Banasik, K., Brumpton, B., Zhou, W., ... DBDS Genomic Consortium (2021). Genetic insight into sick sinus syndrome. European Heart Journal, 42(20), 1959-1971. https://doi.org/10.1093/eurheartj/ehaa1108

CBE

Thorolfsdottir RB, Sveinbjornsson G, Aegisdottir HM, Benonisdottir S, Stefansdottir L, Ivarsdottir EV, Halldorsson GH, Sigurdsson JK, Torp-Pedersen C, Weeke PE, Brunak S, Westergaard D, Pedersen OB, Sorensen E, Nielsen KR, Burgdorf KS, Banasik K, Brumpton B, Zhou W, Oddsson A, Tragante V, Hjorleifsson KE, Davidsson OB, Rajamani S, Jonsson S, Torfason B, Valgardsson AS, Thorgeirsson G, Frigge ML, Thorleifsson G, Norddahl GL, Helgadottir A, Gretarsdottir S, Sulem P, Jonsdottir I, Willer CJ, Hveem K, Bundgaard H, Ullum H, Arnar DO, Thorsteinsdottir U, Gudbjartsson DF, Holm H, Stefansson K, DBDS Genomic Consortium. 2021. Genetic insight into sick sinus syndrome. European Heart Journal. 42(20):1959-1971. https://doi.org/10.1093/eurheartj/ehaa1108

MLA

Vancouver

Thorolfsdottir RB, Sveinbjornsson G, Aegisdottir HM, Benonisdottir S, Stefansdottir L, Ivarsdottir EV et al. Genetic insight into sick sinus syndrome. European Heart Journal. 2021 May 21;42(20):1959-1971. https://doi.org/10.1093/eurheartj/ehaa1108

Author

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. / Genetic insight into sick sinus syndrome. In: European Heart Journal. 2021 ; Vol. 42, No. 20. pp. 1959-1971.

Bibtex

@article{c7f3597304fd4033bffd4080e9cf3275,
title = "Genetic insight into sick sinus syndrome",
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 = "Atrial fibrillation, GWAS, KRT8, Mendelian randomization, Sick sinus syndrome",
author = "Thorolfsdottir, {Rosa B} and Gardar Sveinbjornsson and Aegisdottir, {Hildur M} and Stefania Benonisdottir and Lilja Stefansdottir and Ivarsdottir, {Erna V} and Halldorsson, {Gisli H} and Sigurdsson, {Jon K} and Christian Torp-Pedersen and Weeke, {Peter E} and S{\o}ren Brunak and David Westergaard and Pedersen, {Ole B} and Erik Sorensen and Nielsen, {Kaspar R} and Burgdorf, {Kristoffer S} and Karina Banasik and Ben Brumpton and Wei Zhou and Asmundur Oddsson and Vinicius Tragante and Hjorleifsson, {Kristjan E} and Davidsson, {Olafur B} and Sridharan Rajamani and Stefan Jonsson and Bjarni Torfason and Valgardsson, {Atli S} and Gudmundur Thorgeirsson and Frigge, {Michael L} and Gudmar Thorleifsson and Norddahl, {Gudmundur L} and Anna Helgadottir and Solveig Gretarsdottir and Patrick Sulem and Ingileif Jonsdottir and Willer, {Cristen J} and Kristian Hveem and Henning Bundgaard and Henrik Ullum and Arnar, {David O} and Unnur Thorsteinsdottir and Gudbjartsson, {Daniel F} and Hilma Holm and Kari Stefansson and {DBDS Genomic Consortium}",
note = "{\textcopyright} The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.",
year = "2021",
month = may,
day = "21",
doi = "10.1093/eurheartj/ehaa1108",
language = "English",
volume = "42",
pages = "1959--1971",
journal = "European Heart Journal",
issn = "0195-668X",
publisher = "Oxford University Press",
number = "20",

}

RIS

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 - Sorensen, 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

N1 - © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

PY - 2021/5/21

Y1 - 2021/5/21

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.

KW - Atrial fibrillation

KW - GWAS

KW - KRT8

KW - Mendelian randomization

KW - Sick sinus syndrome

UR - http://www.scopus.com/inward/record.url?scp=85107088568&partnerID=8YFLogxK

U2 - 10.1093/eurheartj/ehaa1108

DO - 10.1093/eurheartj/ehaa1108

M3 - Journal article

C2 - 33580673

VL - 42

SP - 1959

EP - 1971

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

IS - 20

ER -

ID: 62373710