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

TitleIdentification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.
Publication TypeJournal Article
Year of Publication2013
Authorsden Hoed M, Eijgelsheim M, Esko T, Brundel BJJM, Peal DS, Evans DM, Nolte IM, Segrè AV, Holm H, Handsaker RE et al.
Corporate AuthorsGlobal BPgen Consortium, CARDIoGRAM consortium, PR GWAS Consortium, QRS GWAS Consortium, QT-IGC Consortium, CHARGE-AF Consortium
JournalNat Genet
Volume45
Issue6
Pagination621-31
Date Published2013 Jun
ISSN1546-1718
KeywordsAnimals, Arrhythmias, Cardiac, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Heart Rate, Humans, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Quantitative Trait Loci
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.

DOI10.1038/ng.2610
Alternate JournalNat. Genet.
PubMed ID23583979
PubMed Central IDPMC3696959
Grant List092731 / / Wellcome Trust / United Kingdom
CZB/4/710 / / Chief Scientist Office / United Kingdom
G0600705 / / Medical Research Council / United Kingdom
G0801056 / / Medical Research Council / United Kingdom
G1000143 / / Medical Research Council / United Kingdom
G9815508 / / Medical Research Council / United Kingdom
MC_PC_U127561128 / / Medical Research Council / United Kingdom
MC_U106179471 / / Medical Research Council / United Kingdom
MC_U106179472 / / Medical Research Council / United Kingdom
MC_U106179473 / / Medical Research Council / United Kingdom
MC_U106188470 / / Medical Research Council / United Kingdom
MC_U123092720 / / Medical Research Council / United Kingdom
MC_U127592696 / / Medical Research Council / United Kingdom
MC_UP_A100_1003 / / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
PG/11/63/29011 / / British Heart Foundation / United Kingdom
PG/12/38/29615 / / British Heart Foundation / United Kingdom
R00 HL094535 / HL / NHLBI NIH HHS / United States
R01 HL090620 / HL / NHLBI NIH HHS / United States
R01 HL092217 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HL111314 / HL / NHLBI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
U19 HL065962 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States