Abstract
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. 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.
Highlights
We considered for discovery only variants present in >60% of the maximum sample size in the genomewide association studies (GWAS) summary results, a filtering criterion used to ensure robustness of associated loci
We report signals in/near 12 candidate genes at previously not reported loci with functional roles in cytoskeletal assembly (DSP, DES, OBSL1, PDLIM5, LDB3, FHL2, CEFIP, SSPN, TLN2, PTK2, GJA5, and CDH2; Fig. 5)
Mutations in the desmosome are implicated in arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy (DCM)[24,25,26,27,28]
Summary
In a secondary analysis among the European ancestry subset, a total of 127 loci not previously reported reached genome-wide significance We identified missense variants in genes at 11 previously not reported loci, one from the European subset meta-analysis, and 6 previously reported loci (Supplementary Data 12). Analysis of chromatin states indicated variants at 97 previously not reported, 6 European, and 52 previously reported loci were located within regulatory elements that are present in heart tissues (Supplementary Data 15), providing support for gene regulatory mechanisms in specifying the PR interval. Variants at 35 previously not reported and 3 European loci were associated with other traits, including AF and coronary heart disease (Supplementary Data 17, Supplementary Fig. 10). Results were similar when using a PRS derived using the multi-ancestry meta-analysis results (Supplementary Fig. 12, Supplementary Table 2, and Supplementary Data 3)
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