Common variants at ten loci influence QT interval duration in the QTGEN Study.
QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 x 10(-8) with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.
Newton-Cheh
Christopher
C
Center for Human Genetic Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. cnewtoncheh@chgr.mgh.harvard.edu
Eijgelsheim
Mark
M
Rice
Kenneth M
KM
de Bakker
Paul I W
PI
Yin
Xiaoyan
X
Estrada
Karol
K
Bis
Joshua C
JC
Marciante
Kristin
K
Rivadeneira
Fernando
F
Noseworthy
Peter A
PA
Sotoodehnia
Nona
N
Smith
Nicholas L
NL
Rotter
Jerome I
JI
Kors
Jan A
JA
Witteman
Jacqueline C M
JC
Hofman
Albert
A
Heckbert
Susan R
SR
O'Donnell
Christopher J
CJ
Uitterlinden
André G
AG
Psaty
Bruce M
BM
Lumley
Thomas
T
Larson
Martin G
MG
Stricker
Bruno H Ch
BH
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000235:genetics*; D002874:Chromosome Mapping; D016757:Death, Sudden, Cardiac; D000072237:ERG1 Potassium Channel; D004569:Electroencephalography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D015201:Meta-Analysis as Topic; D009124:Muscle Proteins / Q000235:genetics; D062554:NAV1.5 Voltage-Gated Sodium Channel; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D012307:Risk Factors; D015222:Sodium Channels / Q000235:genetics; D044465:White People / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C488081:NOS1AP protein, human; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; D015222:Sodium Channels