Genome- and phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk

Abstract

Background: ECG QRS duration, a measure of cardiac intraventricular conduction, varies ≈2-fold in individuals without cardiac disease. Slow conduction may promote re-entrant arrhythmias.

Methods and results: We performed a genome-wide association study to identify genomic markers of QRS duration in 5272 individuals without cardiac disease selected from electronic medical record algorithms at 5 sites in the Electronic Medical Records and Genomics (eMERGE) network. The most significant loci were evaluated within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium QRS genome-wide association study meta-analysis. Twenty-three single-nucleotide polymorphisms in 5 loci, previously described by CHARGE, were replicated in the eMERGE samples; 18 single-nucleotide polymorphisms were in the chromosome 3 SCN5A and SCN10A loci, where the most significant single-nucleotide polymorphisms were rs1805126 in SCN5A with P=1.2×10(-8) (eMERGE) and P=2.5×10(-20) (CHARGE) and rs6795970 in SCN10A with P=6×10(-6) (eMERGE) and P=5×10(-27) (CHARGE). The other loci were in NFIA, near CDKN1A, and near C6orf204. We then performed phenome-wide association studies on variants in these 5 loci in 13859 European Americans to search for diagnoses associated with these markers. Phenome-wide association study identified atrial fibrillation and cardiac arrhythmias as the most common associated diagnoses with SCN10A and SCN5A variants. SCN10A variants were also associated with subsequent development of atrial fibrillation and arrhythmia in the original 5272 "heart-healthy" study population.

Conclusions: We conclude that DNA biobanks coupled to electronic medical records not only provide a platform for genome-wide association study but also may allow broad interrogation of the longitudinal incidence of disease associated with genetic variants. The phenome-wide association study approach implicated sodium channel variants modulating QRS duration in subjects without cardiac disease as predictors of subsequent arrhythmias.

Figure 1

Panel A. Distribution of QRS durations in 5,272 normal ECGs. Panel B. Genome-wide association analysis of QRS duration, using sex-adjusted linear regression. The red line indicates genome-wide significance (p=5×10⁻⁸). The points in green are those SNPs that were also identified at genome-wide significance in the CHARGE consortium QRS meta-analysis as described in the text.

Figure 2

Phenome-wide association study plots of most significant SNPs associated with QRS duration. Panel A. SCN5A (rs1805126). Panel B. SCN10A (rs6795970). The blue lines indicate p<0.05.

Figure 3

Kaplan-Meier estimate of development Atrial Fibrillation per SCN10A rs6795970 genotype. All patients were judged free of cardiac disease (including arrhythmias) at the time of the initial normal ECG.