Common variants at ten loci modulate the QT interval duration in the QTSCD Study

Abstract

The QT interval, a measure of cardiac repolarization, predisposes to ventricular arrhythmias and sudden cardiac death (SCD) when prolonged or shortened. A common variant in NOS1AP is known to influence repolarization. We analyze genome-wide data from five population-based cohorts (ARIC, KORA, SardiNIA, GenNOVA and HNR) with a total of 15,842 individuals of European ancestry, to confirm the NOS1AP association and identify nine additional loci at P < 5 x 10(-8). Four loci map near the monogenic long-QT syndrome genes KCNQ1, KCNH2, SCN5A and KCNJ2. Two other loci include ATP1B1 and PLN, genes with established electrophysiological function, whereas three map to RNF207, near LITAF and within NDRG4-GINS3-SETD6-CNOT1, respectively, all of which have not previously been implicated in cardiac electrophysiology. These results, together with an accompanying paper from the QTGEN consortium, identify new candidate genes for ventricular arrhythmias and SCD.

Figure 1

Manhattan and quantile-quantile plots of genome-wide association analyses. Genome-wide association results were combined across all studies by inverse variance weighting. The blue dotted line marks the threshold for genome-wide significance (5 × 10⁻⁸). SNPs within loci exceeding this threshold are highlighted in green. The upper right panel shows the quantile-quantile plot, where the red line corresponds to all test values, the orange line corresponds to results after excluding SNPs at NOS1AP and the blue line to results after excluding SNPs at all associated loci (highlighted in green in the Manhattan plot). The gray area corresponds to the 90% confidence region of the null distribution of P values (generated from 100 simulations).

Figure 2

Association results at each significant locus. (a–j) The gene locus is from left to right: RNF207, NOS1AP, ATP1B, SCN5A, SLC35F1-PLN-C6orf204, KCNH2, KCNQ1, LITAF, GINS3-NDRG4-SETD6-CNOT1 and KCNJ2. Each panel spans ± 500 kb around each SNP except for panel A (300 kb), panel B, panel C, panel E (600 kb) and panel J (800 kb). At the top of each panel, the location and density of SNPs in the Illumina HumanHap 550K, Affymetrix 500K chips, and imputed SNPs are shown. The SNPs are colored according to their linkage disequilibrium with the leading variant, which is highlighted with a blue square. SNPs representing independent signals from the leading variant are highlighted with a purple diamond. Gene transcripts are annotated in the lower box, + or −, indicating the direction of transcription. In panel F, some gene names are omitted for clarity.

Figure 3

Combined effect of the QT interval–prolonging alleles in the studies of unrelated individuals. Individuals were classified by counting their number of QT-prolonging alleles in all ten identified markers (max score 20). Dosages for the QT-prolonging allele as calculated by MACH1 were added and then rounded to the nearest integer. Gray bars indicate the number of individuals in each score class, blue dots indicate the mean QT interval for each class, and the black line is the linear regression though these points.