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

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 - Olsen, Jesper V

AU - Global BPgen 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.

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 -