Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

Abstract

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

Figure 1. Manhattan plot

Manhattan plot showing the association of SNPs with QRS interval duration in a GWAS of 40,407 individuals. The dashed horizontal line marks the threshold for genome-wide significance (P = 5 × 10⁻⁸). Twenty loci (labeled) reached genome-wide significance. Two additional loci, GOSR2 and DKK1, reached significance after genotyping of select SNPs in an additional sample of 7170 individuals (see Results).

Figure 2. Association plots for select loci

Each SNP is plotted with respect to its chromosomal location (x-axis) and its P-value (y-axis on the left). The tall blue spikes indicate the recombination rate (y-axis on the right) at that region of the chromosome. The blue-outlined triangles indicate coding region SNPs. (a) Locus 1 (SCN5A/SCN10A) on chromosome 3: The six index signals are named with their rs numbers and highlighted in different colors (yellow, green, teal, blue, purple, and red). Other SNPs in linkage disequilibrium with the index SNP are denoted in the same color. Color saturation indicates the degree of correlation with the index SNP. (b) Locus 8 (TBX5) and locus 9 (TBX3) on chromosome 12. (c) Locus 12 (HEATR5B/STRN) and locus 14 (CRIM1) on chromosome 2.

Figure 3. Pleiotropic associations of PR, QRS, and QT loci

Electrocardiographic tracing delineating the PR, QRS, and QT intervals. PR and QRS intervals reflect myocardial depolarization and conduction time through the atria and down the atrioventricular node (PR) and throughout the ventricle (QRS), and are weakly positively correlated (r=0.09). The majority of loci that influence both PR and QRS (SCN5A, SCN10A, TBX5, CAV1/2), do so in a concordant fashion (i.e. variants that prolong PR also prolong QRS duration). The notable exception is a region on chromosome 12, where variants in the TBX5 locus have a concordant effect whereas those in nearby TBX3 have a discordant effect. By contrast, although QRS (ventricular depolarization) and QT (ventricular repolarization) are moderately positively correlated, the majority of loci (SCN5A, SCN10A, PRKCA, NOS1AP) that influence both phenotypes do so in a discordant fashion (i.e. variants that prolong QRS shorten the QT interval). The exception is the locus at PLN, where variants have a concordant effect.

Figure 4. Expression and function of Scn10a in the murine heart

Panel A. Neonatal ventricular myocytes from Cntn2-EGFP BAC transgenic mice were FACS sorted and EGFP+ and EGFP- pools were analyzed by RT-PCR. Transcripts encoding EGFP, Cntn2 and Scn10a were highly enriched in the EGFP+ fraction. Quantitative RT-PCR demonstrated 25.7 fold enrichment of Scn10a/Na_v1.8. Panel B. Representative telemetric electrocardiographic recordings (lead II configuration) obtained 30 minutes after administration of vehicle alone (black tracing) or the Scn10a/Nav1.8 antagonist A-803467 (green tracing). The two tracings are aligned at the onset of the QRS wave and both PR interval and QRS interval prolongation were observed in drug-treated mice. Panel C. Representative intracardiac recordings showing HV intervals obtained prior to (Pre) and after (Post) administration of vehicle or A-803467. Significant HV prolongation was observed in drug-treated mice.