Abstract
BACKGROUND: The PR interval on the ECG reflects atrial depolarization and atrioventricular nodal delay which can be partially differentiated by P wave duration and PR segment, respectively. Genome-wide association studies have identified several genetic loci for PR interval, but it remains to be determined whether this is driven by P wave duration, PR segment, or both. METHODS AND RESULTS: We replicated 7 of the 9 known PR interval loci in 16 468 individuals of European ancestry. Four loci were unambiguously associated with PR segment, while the others were shared for P wave duration and PR segment. Next, we performed a genome-wide analysis on P wave duration and PR segment separately and identified 5 novel loci. Single-nucleotide polymorphisms in KCND3 (P=8.3×10(-11)) and FADS2 (P=2.7×10(-8)) were associated with P wave duration, whereas single-nucleotide polymorphisms near IL17D (P=2.3×10(-8)), in EFHA1 (P=3.3×10(-10)), and in LRCH1 (P=2.1×10(-8)) were associated with PR segment. Analysis on DNA elements indicated that genome-wide significant single-nucleotide polymorphisms were enriched at genomic regions suggesting active gene transcription in the human right atrium. Quantitative polymerase chain reaction showed that genes were significantly higher expressed in the right atrium and atrioventricular node compared with left ventricle (P=5.6×10(-6)). CONCLUSIONS: Genetic associations of PR interval seem to be mainly driven by genetic determinants of the PR segment. Some of the PR interval associations are strengthened by a directional consistent effect of genetic determinants of P wave duration. Through genome-wide association we also identified genetic variants specifically associated with P wave duration which might be relevant for cardiac biology.