Abstract
Features of the QRS complex of the electrocardiogram, reflecting ventricular depolarisation, associate with various physiologic functions and several pathologic conditions. We test 32.5 million variants for association with ten measures of the QRS complex in 12 leads, using 405,732 electrocardiograms from 81,192 Icelanders. We identify 190 associations at 130 loci, the majority of which have not been reported before, including associations with 21 rare or low-frequency coding variants. Assessment of genes expressed in the heart yields an additional 13 rare QRS coding variants at 12 loci. We find 51 unreported associations between the QRS variants and echocardiographic traits and cardiovascular diseases, including atrial fibrillation, complete AV block, heart failure and supraventricular tachycardia. We demonstrate the advantage of in-depth analysis of the QRS complex in conjunction with other cardiovascular phenotypes to enhance our understanding of the genetic basis of myocardial mass, cardiac conduction and disease.
Highlights
Features of the QRS complex of the electrocardiogram, reflecting ventricular depolarisation, associate with various physiologic functions and several pathologic conditions
We found three associations with complete AV block (CAVB), represented by p.Glu382Asp in CCDC141 (MAF = 15.3%, OR = 1.29, P = 3.6 × 10−7), which associates with pacemaker insertion (OR = 1.12, P = 5.9 × 10−5) and sinus syndrome (SSS) (OR = 1.13, P = 2.1 × 10−4); rs4794562[T] intronic to HLF (MAF = 25.7%, OR = 0.86, P = 7.8 × 10−4), which associates with heart failure (OR = 0.95, P = 6.7 × 10−5); and rs17226667[A] near CEP85L (MAF = 45.8%, OR = 1.13, P = 8.1 × 10−4)
We found 190 distinct QRS variants, of which 106 are at 86 loci that have not been reported for QRS before, and assessed their effects on seven echocardiographic traits and 22 cardiovascular diseases
Summary
Features of the QRS complex of the electrocardiogram, reflecting ventricular depolarisation, associate with various physiologic functions and several pathologic conditions. The QRS complex (Fig. 1) of the electrocardiogram (ECG) is a summation of electrical activity in the heart during ventricular depolarisation. Prior genome-wide association studies (GWAS) of the QRS complex were limited to testing QRS duration and voltage criteria reflecting left ventricular hypertrophy, yielding sequence variants at 58 loci with minor allele frequency (MAF) >4%10–15. To gain a better understanding of the molecular mechanism of ventricular conduction, we perform a large GWAS of ten measures of the QRS complex in 12 leads from ECGs of 81,192 individuals. We demonstrate the advantage of analysing 12 leads of the ECG and identify rare protein-coding variants in genes that can improve the understanding of risk and progression of heart disease and help direct future studies
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