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; Jesper V Olsen; Global BPgen Consortium

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, Jesper V Olsen, Global BPgen Consortium

Novo Nordisk Foundation Center for Protein Research

187 Citations (Scopus)

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
Journal	Nature Genetics
Volume	45
Issue number	6
Pages (from-to)	621-631
Number of pages	11
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.2610
Publication status	Published - Jun 2013

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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., ... Global BPgen Consortium (2013). Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nature Genetics, 45(6), 621-631. https://doi.org/10.1038/ng.2610

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, Olsen, JV & Global BPgen Consortium 2013, 'Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders', Nature Genetics, vol. 45, no. 6, pp. 621-631. https://doi.org/10.1038/ng.2610

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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.",

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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 - Olsen, Jesper V

AU - Global BPgen Consortium

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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.

U2 - 10.1038/ng.2610

DO - 10.1038/ng.2610

M3 - Journal article

C2 - 23583979

SN - 1061-4036

VL - 45

SP - 621

EP - 631

JO - Nature: New biology

JF - Nature: New biology

IS - 6

ER -

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

Abstract

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