Genetic insight into sick sinus syndrome

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; Thomas Mears Werge; Poul Jørgen Jennum; DBDS Genomic Consortium; Pär Ingemar Johansson; DBDS Genomic Consortium; Thomas Folkmann Hansen; Poul Jørgen Jennum; Henrik Hjalgrim

doi:10.1093/eurheartj/ehaa1108

Genetic insight into sick sinus syndrome

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 OddssonVinicius 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, Thomas Mears Werge (Medlem af forfattergruppering), Poul Jørgen Jennum (Medlem af forfattergruppering), DBDS Genomic Consortium, Pär Ingemar Johansson (Medlem af forfattergruppering), DBDS Genomic Consortium , Thomas Folkmann Hansen (Medlem af forfattergruppering), Poul Jørgen Jennum (Medlem af forfattergruppering), Henrik Hjalgrim (Medlem af forfattergruppering)

41 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	European Heart Journal
Vol/bind	42
Udgave nummer	20
Sider (fra-til)	1959-1971
Antal sider	13
ISSN	0195-668X
DOI	https://doi.org/10.1093/eurheartj/ehaa1108
Status	Udgivet - 21 maj 2021

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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., ... Hjalgrim, H. (2021). Genetic insight into sick sinus syndrome. European Heart Journal, 42(20), 1959-1971. https://doi.org/10.1093/eurheartj/ehaa1108

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, Werge, TM , Jennum, PJ, DBDS Genomic Consortium, Johansson, PI, DBDS Genomic Consortium , Hansen, TF , Jennum, PJ & Hjalgrim, H 2021, 'Genetic insight into sick sinus syndrome', European Heart Journal, bind 42, nr. 20, s. 1959-1971. https://doi.org/10.1093/eurheartj/ehaa1108

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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/genetics, Diabetes Mellitus, Type 2, Genome-Wide Association Study, Humans, NAV1.8 Voltage-Gated Sodium Channel, Pacemaker, Artificial, Sick Sinus Syndrome/genetics",

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 Werge, {Thomas Mears} and Jennum, {Poul J{\o}rgen} and {DBDS Genomic Consortium} and Johansson, {P{\"a}r Ingemar} and {DBDS Genomic Consortium} and Hansen, {Thomas Folkmann} and Jennum, {Poul J{\o}rgen} and Henrik Hjalgrim",

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",

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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 - 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

A2 - Werge, Thomas Mears

A2 - Jennum, Poul Jørgen

A2 - Johansson, Pär Ingemar

A2 - Hansen, Thomas Folkmann

A2 - Jennum, Poul Jørgen

A2 - Hjalgrim, Henrik

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/genetics

KW - Diabetes Mellitus, Type 2

KW - Genome-Wide Association Study

KW - Humans

KW - NAV1.8 Voltage-Gated Sodium Channel

KW - Pacemaker, Artificial

KW - Sick Sinus Syndrome/genetics

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

SN - 0195-668X

VL - 42

SP - 1959

EP - 1971

JO - European Heart Journal

JF - European Heart Journal

IS - 20

ER -

Genetic insight into sick sinus syndrome

Abstract

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