Common variants at ten loci influence QT interval duration in the QTGEN Study

Abstract

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.

Figure 1

QT interval association results for 2,543,686 imputed SNPs in 13,685 individuals from 3 cohorts. Results are shown on the −log10(P) scale and are truncated at −log10(P) = 18 for display purposes. The solid bar corresponds to the genome-wide significance threshold of 5×10⁻⁸.

Figure 2

Regional association plots for one megabase surrounding each associated locus. Statistical significance of associated SNPs at each locus are shown on the -log(P) scale as a function of chromosomal position (NCBI Build 36). The primary associated SNP at each locus is shown in red. The correlation of the primary SNP to other SNPs at the locus is shown on a scale from minimal (white) to maximal (bright red). The quality of imputation as assessed by the observed/expected variance on allele dosage is represented by the darkness of the diamond outline ranging from maximal (black) to minimal (light gray). Estimated recombination rates from HapMap and RefSeq annotations are shown. The loci shown include: (a) 1q23.3 including NOS1AP with three independent associations, rs12143842 in red, rs12029454 in green and rs16857031 in blue, (b) 11p15.5 including KCNQ1 with two independent associations, rs2074238 in green and rs12576329 in red, (c) 16q21 including GINS3, NDRG4 and CNOT1, (d) 6q22.31 including c6orf204 and PLN, (e) 1p36.31 including RNF207, (f) 7q36.1 including KCNH2 with two independent associations, rs4725982 in red and rs2968864 in green, (g) 16p13.3 including LITAF, (h) 21q22.12 including KCNE1, (i) 3p22.2 including SCN5A and (j) 17q12 including LIG3 and RFFL.