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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
AuthorsHoed Mden, Eijgelsheim M, Esko T, et al.
Secondary AuthorsLoos RJF
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 ListCZB/4/710 / / Chief Scientist Office / United Kingdom
G0801056 / / Medical Research Council / United Kingdom
K24 HL105780 / HL / NHLBI NIH HHS / United States
R01 HL092217 / HL / NHLBI NIH HHS / United States
G0600705 / / Medical Research Council / United Kingdom
MC_UP_A100_1003 / / Medical Research Council / United Kingdom
MC_UU_12013/3 / / Medical Research Council / United Kingdom
U19 HL065962 / HL / NHLBI NIH HHS / United States
092731 / / Wellcome Trust / United Kingdom
G1000143 / / Medical Research Council / United Kingdom
T32 GM007753 / GM / NIGMS NIH HHS / United States
MC_U106179473 / / Medical Research Council / United Kingdom
UL1 TR000124 / TR / NCATS NIH HHS / United States
R01 HL090620 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
MC_U106179471 / / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
MC_UU_12015/2 / / Medical Research Council / United Kingdom
R21 DA026982 / DA / NIDA NIH HHS / United States
MC_PC_15018 / / Medical Research Council / United Kingdom
MC_U123092720 / / Medical Research Council / United Kingdom
MC_U106179472 / / Medical Research Council / United Kingdom
G1002084 / / Medical Research Council / United Kingdom
MC_PC_U127592696 / / Medical Research Council / United Kingdom
G0401527 / / Medical Research Council / United Kingdom
MC_UU_12013/1 / / Medical Research Council / United Kingdom
R01 HL111314 / HL / NHLBI NIH HHS / United States
R00 HL094535 / HL / NHLBI NIH HHS / United States
MC_UU_12013/4 / / Medical Research Council / United Kingdom
MC_PC_U127561128 / / Medical Research Council / United Kingdom
P30 DK020572 / DK / NIDDK NIH HHS / United States
MC_U127592696 / / Medical Research Council / United Kingdom
MC_U106188470 / / Medical Research Council / United Kingdom
PG/12/38/29615 / / British Heart Foundation / United Kingdom
G9815508 / / Medical Research Council / United Kingdom