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

Marcel den Hoed; Mark Eijgelsheim; Tonu Esko; Bianca J. J. M. Brundel; David S. Peal; David M. Evans; Ilja M. Nolte; Ayellet V. Segre; 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; Zoltan Kutalik; Jian'an Luan; John P. Kemp; Kati Kristiansson; Toshiko Tanaka; Femke Hoogstra-Berends; Bart Kanon; Meena Kumari; Irene Mateo Leach; Albert V. Smith; Cisca Wijmenga; Rudolf A. de Boer; Wiek H. van Gilst; Melanie M. van der Klauw; Gerjan Navis; Lu Qi; Ronald P. Stolk; Dirk J. van Veldhuisen; Lude Franke; Ody C. M. Sibon; Harold Snieder; Global BPGen Consortium; CARDIoGRAM Consortium; PR GWGWAS Consortium; QRS GWGWAS Consortium; QT-IGCGC Consortium; CHARGE-AF 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, Tonu Esko, Bianca J. J. M. Brundel, David S. Peal, David M. Evans, Ilja M. Nolte, Ayellet V. Segre, 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, Zoltan Kutalik, Jian'an Luan, John P. Kemp, Kati Kristiansson, Toshiko Tanaka, Femke Hoogstra-Berends, Bart Kanon, Meena Kumari, Irene Mateo Leach, Albert V. Smith, Cisca Wijmenga, Rudolf A. de Boer, Wiek H. van Gilst, Melanie M. van der Klauw, Gerjan Navis, Lu Qi, Ronald P. Stolk, Dirk J. van Veldhuisen, Lude Franke, Ody C. M. Sibon, Harold Snieder, Global BPGen Consortium, CARDIoGRAM Consortium, PR GWGWAS Consortium, QRS GWGWAS Consortium, QT-IGCGC Consortium, CHARGE-AF Consortium

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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.

Originele taal-2	English
Pagina's (van-tot)	621-31
Aantal pagina's	11
Tijdschrift	Nature Genetics
Volume	45
Nummer van het tijdschrift	6
DOI's	https://doi.org/10.1038/ng.2610
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., Segre, 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., ... CHARGE-AF Consortium (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{cf798a6bbc25430784b7f7853a4d116d,

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 = "GENOME-WIDE ASSOCIATION, COMMON VARIANTS, SUSCEPTIBILITY LOCI, ATRIAL-FIBRILLATION, QRS DURATION, QT INTERVAL, PR INTERVAL, DISEASE, DROSOPHILA, LIBRARY",

author = "{den Hoed}, Marcel and Mark Eijgelsheim and Tonu Esko and Brundel, {Bianca J. J. M.} and Peal, {David S.} and Evans, {David M.} and Nolte, {Ilja M.} and Segre, {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 Zoltan Kutalik and Jian'an Luan and Kemp, {John P.} and Kati Kristiansson and Toshiko Tanaka and Femke Hoogstra-Berends and Bart Kanon and Meena Kumari and {Mateo Leach}, Irene and Smith, {Albert V.} and Cisca Wijmenga and {de Boer}, {Rudolf A.} and {van Gilst}, {Wiek H.} and {van der Klauw}, {Melanie M.} and Gerjan Navis and Lu Qi and Stolk, {Ronald P.} and {van Veldhuisen}, {Dirk J.} and Lude Franke and Sibon, {Ody C. M.} and Harold Snieder and {Global BPGen Consortium} and {CARDIoGRAM Consortium} and {PR GWGWAS Consortium} and {QRS GWGWAS Consortium} and {QT-IGCGC Consortium} and {CHARGE-AF Consortium}",

year = "2013",

month = jun,

doi = "10.1038/ng.2610",

language = "English",

volume = "45",

pages = "621--31",

journal = "Nature Genetics",

publisher = "Nature Publishing Group",

number = "6",

}

den Hoed, M, Eijgelsheim, M, Esko, T, Brundel, BJJM, Peal, DS, Evans, DM, Nolte, IM, Segre, 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, Tanaka, T, Hoogstra-Berends, F , Kanon, B, Kumari, M, Mateo Leach, I, Smith, AV, Wijmenga, C , de Boer, RA , van Gilst, WH , van der Klauw, MM , Navis, G, Qi, L, Stolk, RP , van Veldhuisen, DJ , Franke, L , Sibon, OCM , Snieder, H, Global BPGen Consortium, CARDIoGRAM Consortium, PR GWGWAS Consortium, QRS GWGWAS Consortium, QT-IGCGC Consortium & CHARGE-AF Consortium 2013, 'Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders', Nature Genetics, vol. 45, nr. 6, blz. 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, Tonu

AU - Brundel, Bianca J. J. M.

AU - Peal, David S.

AU - Evans, David M.

AU - Nolte, Ilja M.

AU - Segre, 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, Zoltan

AU - Luan, Jian'an

AU - Kemp, John P.

AU - Kristiansson, Kati

AU - Tanaka, Toshiko

AU - Hoogstra-Berends, Femke

AU - Kanon, Bart

AU - Kumari, Meena

AU - Mateo Leach, Irene

AU - Smith, Albert V.

AU - Wijmenga, Cisca

AU - de Boer, Rudolf A.

AU - van Gilst, Wiek H.

AU - van der Klauw, Melanie M.

AU - Navis, Gerjan

AU - Qi, Lu

AU - Stolk, Ronald P.

AU - van Veldhuisen, Dirk J.

AU - Franke, Lude

AU - Sibon, Ody C. M.

AU - Snieder, Harold

AU - Global BPGen Consortium

AU - CARDIoGRAM Consortium

AU - PR GWGWAS Consortium

AU - QRS GWGWAS Consortium

AU - QT-IGCGC Consortium

AU - CHARGE-AF Consortium

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 - GENOME-WIDE ASSOCIATION

KW - COMMON VARIANTS

KW - SUSCEPTIBILITY LOCI

KW - ATRIAL-FIBRILLATION

KW - QRS DURATION

KW - QT INTERVAL

KW - PR INTERVAL

KW - DISEASE

KW - DROSOPHILA

KW - LIBRARY

U2 - 10.1038/ng.2610

DO - 10.1038/ng.2610

M3 - Article

C2 - 23583979

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

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