In a meta-analysis of nearly 300,000 individuals, UK co-led research has identified over 200 loci, almost two-thirds of which were previously unreported underlying cardiac conduction as manifested by the electrocardiographic PR interval.
Collectively, the results represent a major advance in understanding the polygenic nature of cardiac conduction and the genetic relationship between PR interval duration and arrhythmias, the researchers said.
The study, published in Nature Communications, reports a multi-ancestry (n=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5 per cent to 62.6 per cent.
The researchers observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction.
Additionally, eight loci not previously reported harbour genes underlying inherited arrhythmic syndromes and/or cardiomyopathies, suggesting a role for these genes in cardiovascular pathology in the general population.
The study indicates that common variation in Mendelian cardiovascular disease genes contributes to population-based variation in the PR interval.
Apart from confirming well-established associations in loci harboring ion-channel genes, the findings further underscore the central importance of heart development and cytoskeletal components in atrioventricular conduction, the researchers said. The findings also highlight the role of common variation at loci harbouring genes underlying monogenic forms of arrhythmias and cardiomyopathies in cardiac conduction.
The research essentially shows that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, atrial fibrillation, and atrioventricular pre-excitation, the authors said.
The results could one day lead to advanced screening methods to discern who is at greatest risk of developing disease, and could help reveal new genetic targets for research and drug development.