Researchers at Queen Mary University of London, the Broad Institute of MIT, and Harvard have found hundreds of new links between people’s DNA and the heart’s electrical activity, according to a study of almost 300,000 people. The research “Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction” is described in Nature Communications.
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.
Over the past 10 years, researchers have identified many genetic factors that contribute to—or protect against—the onset of specific heart diseases. However, it has been difficult to find genetic factors associated with arrhythmias, one of the most common forms of heart disease where the heart beats abnormally.
The team of scientists from more than 140 institutions looked at data from 293,051 people across the world, studying their individual genomes and their measurements on an electrocardiogram.
The researchers specifically studied the length of time between two points on the electrocardiogram read-out known as the “PR interval,” which is associated with a number of common electrical disorders such as atrial fibrillation and other arrhythmias.
The team reported report 202 locations in the genome with links to this type of electrical activity in the heart—141 of which had not been previously identified. This more than triples the number of known genetic regions linked to this type of electrical activity and explains about 62 percent of its heritability.
“The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report 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% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction,” write the investigators.
“Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation.”
“These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.”
“This is the largest global study of its kind to investigate the genetic basis of the PR interval, a well-established electrocardiogram risk marker for heart disease and mortality,” said Patricia Munroe, PhD, co-lead researcher from Queen Mary’s William Harvey Research Institute. “The insights provide new knowledge on biological processes relating to the heart’s electrical activity and potential avenues of drug research for preventing and treating heart conditions.”
“That’s really a striking discovery that wouldn’t have been possible a few years ago,” added Steven Lubitz, MD, from Massachusetts General Hospital and the Broad Institute. “But thanks to many studies, including the UK Biobank, we now have all this imaging and electrocardiogram data paired with genetic data, which has proven to be a really powerful combination.”
The findings indicate that an individual’s inherited predisposition to heart disease is not the result of single-gene mutations, but rather a cumulative effect of many variants across the genome.