Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders

Marcel den Hoed; Mark Eijgelsheim; Tõnu Esko; Bianca J J M Brundel; David S Peal; David M Evans; Ilja M Nolte; Ayellet V Segrè; Hilma Holm; Robert E Handsaker; Harm-Jan Westra; Toby Johnson; Aaron Isaacs; Jian Yang; Alicia Lundby; Jing Hua Zhao; Young Jin Kim; Min Jin Go; Peter Almgren; Murielle Bochud; Gabrielle Boucher; Marilyn C Cornelis; Daniel Gudbjartsson; David Hadley; Pim van der Harst; Caroline Hayward; Martin den Heijer; Wilmar Igl; Anne U Jackson; Zoltán Kutalik; Jian'an Luan; John P Kemp; Kati Kristiansson; Claes Ladenvall; Mattias Lorentzon; May E Montasser; Omer T Njajou; Paul F O'Reilly; Sandosh Padmanabhan; Beate St Pourcain; Tuomo Rankinen; Perttu Salo; Toshiko Tanaka; Nicholas J Timpson; Veronique Vitart; Lindsay Waite; William Wheeler; Weihua Zhang; Harmen H M Draisma; Andrew Wong; Global BPgen Consortium; Ruth J. F. Loos

doi:10.1038/ng.2610

Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders

Marcel den Hoed, Mark Eijgelsheim, Tõnu Esko, Bianca J J M Brundel, David S Peal, David M Evans, Ilja M Nolte, Ayellet V Segrè, Hilma Holm, Robert E Handsaker, Harm-Jan Westra, Toby Johnson, Aaron Isaacs, Jian Yang, Alicia Lundby, Jing Hua Zhao, Young Jin Kim, Min Jin Go, Peter Almgren, Murielle BochudGabrielle Boucher, Marilyn C Cornelis, Daniel Gudbjartsson, David Hadley, Pim van der Harst, Caroline Hayward, Martin den Heijer, Wilmar Igl, Anne U Jackson, Zoltán Kutalik, Jian'an Luan, John P Kemp, Kati Kristiansson, Claes Ladenvall, Mattias Lorentzon, May E Montasser, Omer T Njajou, Paul F O'Reilly, Sandosh Padmanabhan, Beate St Pourcain, Tuomo Rankinen, Perttu Salo, Toshiko Tanaka, Nicholas J Timpson, Veronique Vitart, Lindsay Waite, William Wheeler, Weihua Zhang, Harmen H M Draisma, Andrew Wong, Global BPgen Consortium, Ruth J. F. Loos^*

^*Corresponding author for this work

Humane Biologie

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Original language	English
Pages (from-to)	621-31
Number of pages	11
Journal	Nature Genetics
Volume	45
Issue number	6
DOIs	https://doi.org/10.1038/ng.2610
Publication status	Published - Jun 2013

Keywords

Animals
Arrhythmias, Cardiac/genetics
Gene Frequency
Genetic Loci
Genome-Wide Association Study
Heart Conduction System/physiopathology
Heart Rate/genetics
Humans
Metabolic Networks and Pathways
Polymorphism, Single Nucleotide
Quantitative Trait Loci

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den Hoed, M., Eijgelsheim, M., Esko, T., Brundel, B. J. J. M., Peal, D. S., Evans, D. M., Nolte, I. M., Segrè, A. V., Holm, H., Handsaker, R. E., Westra, H.-J., Johnson, T., Isaacs, A., Yang, J., Lundby, A., Zhao, J. H., Kim, Y. J., Go, M. J., Almgren, P., ... Loos, R. J. F. (2013). Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nature Genetics, 45(6), 621-31. https://doi.org/10.1038/ng.2610

@article{f3a49f15351c41a38ed277cb038dfbdb,

title = "Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders",

abstract = "Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.",

keywords = "Animals, Arrhythmias, Cardiac/genetics, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Heart Conduction System/physiopathology, Heart Rate/genetics, Humans, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Quantitative Trait Loci",

author = "{den Hoed}, Marcel and Mark Eijgelsheim and T{\~o}nu Esko and Brundel, {Bianca J J M} and Peal, {David S} and Evans, {David M} and Nolte, {Ilja M} and Segr{\`e}, {Ayellet V} and Hilma Holm and Handsaker, {Robert E} and Harm-Jan Westra and Toby Johnson and Aaron Isaacs and Jian Yang and Alicia Lundby and Zhao, {Jing Hua} and Kim, {Young Jin} and Go, {Min Jin} and Peter Almgren and Murielle Bochud and Gabrielle Boucher and Cornelis, {Marilyn C} and Daniel Gudbjartsson and David Hadley and {van der Harst}, Pim and Caroline Hayward and {den Heijer}, Martin and Wilmar Igl and Jackson, {Anne U} and Zolt{\'a}n Kutalik and Jian'an Luan and Kemp, {John P} and Kati Kristiansson and Claes Ladenvall and Mattias Lorentzon and Montasser, {May E} and Njajou, {Omer T} and O'Reilly, {Paul F} and Sandosh Padmanabhan and {St Pourcain}, Beate and Tuomo Rankinen and Perttu Salo and Toshiko Tanaka and Timpson, {Nicholas J} and Veronique Vitart and Lindsay Waite and William Wheeler and Weihua Zhang and Draisma, {Harmen H M} and Andrew Wong and {Global BPgen Consortium} and Loos, {Ruth J. F.}",

year = "2013",

month = jun,

doi = "10.1038/ng.2610",

language = "English",

volume = "45",

pages = "621--31",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

den Hoed, M, Eijgelsheim, M, Esko, T, Brundel, BJJM, Peal, DS, Evans, DM, Nolte, IM, Segrè, AV, Holm, H, Handsaker, RE, Westra, H-J, Johnson, T, Isaacs, A, Yang, J, Lundby, A, Zhao, JH, Kim, YJ, Go, MJ, Almgren, P, Bochud, M, Boucher, G, Cornelis, MC, Gudbjartsson, D, Hadley, D, van der Harst, P, Hayward, C, den Heijer, M, Igl, W, Jackson, AU, Kutalik, Z, Luan, J, Kemp, JP, Kristiansson, K, Ladenvall, C, Lorentzon, M, Montasser, ME, Njajou, OT, O'Reilly, PF, Padmanabhan, S, St Pourcain, B, Rankinen, T, Salo, P, Tanaka, T, Timpson, NJ, Vitart, V, Waite, L, Wheeler, W, Zhang, W, Draisma, HHM, Wong, A, Global BPgen Consortium & Loos, RJF 2013, 'Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders', Nature Genetics, vol. 45, no. 6, pp. 621-31. https://doi.org/10.1038/ng.2610

TY - JOUR

T1 - Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders

AU - den Hoed, Marcel

AU - Eijgelsheim, Mark

AU - Esko, Tõnu

AU - Brundel, Bianca J J M

AU - Peal, David S

AU - Evans, David M

AU - Nolte, Ilja M

AU - Segrè, Ayellet V

AU - Holm, Hilma

AU - Handsaker, Robert E

AU - Westra, Harm-Jan

AU - Johnson, Toby

AU - Isaacs, Aaron

AU - Yang, Jian

AU - Lundby, Alicia

AU - Zhao, Jing Hua

AU - Kim, Young Jin

AU - Go, Min Jin

AU - Almgren, Peter

AU - Bochud, Murielle

AU - Boucher, Gabrielle

AU - Cornelis, Marilyn C

AU - Gudbjartsson, Daniel

AU - Hadley, David

AU - van der Harst, Pim

AU - Hayward, Caroline

AU - den Heijer, Martin

AU - Igl, Wilmar

AU - Jackson, Anne U

AU - Kutalik, Zoltán

AU - Luan, Jian'an

AU - Kemp, John P

AU - Kristiansson, Kati

AU - Ladenvall, Claes

AU - Lorentzon, Mattias

AU - Montasser, May E

AU - Njajou, Omer T

AU - O'Reilly, Paul F

AU - Padmanabhan, Sandosh

AU - St Pourcain, Beate

AU - Rankinen, Tuomo

AU - Salo, Perttu

AU - Tanaka, Toshiko

AU - Timpson, Nicholas J

AU - Vitart, Veronique

AU - Waite, Lindsay

AU - Wheeler, William

AU - Zhang, Weihua

AU - Draisma, Harmen H M

AU - Wong, Andrew

AU - Global BPgen Consortium

AU - Loos, Ruth J. F.

PY - 2013/6

Y1 - 2013/6

N2 - Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

AB - Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

KW - Animals

KW - Arrhythmias, Cardiac/genetics

KW - Gene Frequency

KW - Genetic Loci

KW - Genome-Wide Association Study

KW - Heart Conduction System/physiopathology

KW - Heart Rate/genetics

KW - Humans

KW - Metabolic Networks and Pathways

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

U2 - 10.1038/ng.2610

DO - 10.1038/ng.2610

M3 - Article

C2 - 23583979

SN - 1061-4036

VL - 45

SP - 621

EP - 631

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders

Abstract

Keywords

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