Abstract
Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
Highlights
GWiS estimated 61 non-redundant signals of association at the 40 genome-wide significant loci (Supplementary Data 4)
We examined eQTL associations from LAA and validated findings in tissue from right atrial appendage (RAA)
Expression of each gene was adjusted by the following covariates: sex, genetic substructure based on four multidimensional scaling factors, and 25 expression surrogate variable analysis (SVA) covariates
Summary
GWiS estimated 61 non-redundant signals of association at the 40 genome-wide significant loci (Supplementary Data 4). We performed an eQTL analysis using the 61 PR index SNPs. We examined eQTL associations from LAA and validated findings in tissue from right atrial appendage (RAA).
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