Investigating the Genetic Architecture of the PR Interval Using Clinical Phenotypes

Circ Cardiovasc Genet. 2017 Apr;10(2):e001482. doi: 10.1161/CIRCGENETICS.116.001482.

Abstract

Background: One potential use for the PR interval is as a biomarker of disease risk. We hypothesized that quantifying the shared genetic architectures of the PR interval and a set of clinical phenotypes would identify genetic mechanisms contributing to PR variability and identify diseases associated with a genetic predictor of PR variability.

Methods and results: We used ECG measurements from the ARIC study (Atherosclerosis Risk in Communities; n=6731 subjects) and 63 genetically modulated diseases from the eMERGE network (Electronic Medical Records and Genomics; n=12 978). We measured pairwise genetic correlations (rG) between PR phenotypes (PR interval, PR segment, P-wave duration) and each of the 63 phenotypes. The PR segment was genetically correlated with atrial fibrillation (rG=-0.88; P=0.0009). An analysis of metabolic phenotypes in ARIC also showed that the P wave was genetically correlated with waist circumference (rG=0.47; P=0.02). A genetically predicted PR interval phenotype based on 645 714 single-nucleotide polymorphisms was associated with atrial fibrillation (odds ratio=0.89 per SD change; 95% confidence interval, 0.83-0.95; P=0.0006). The differing pattern of associations among the PR phenotypes is consistent with analyses that show that the genetic correlation between the P wave and PR segment was not significantly different from 0 (rG=-0.03 [0.16]).

Conclusions: The genetic architecture of the PR interval comprises modulators of atrial fibrillation risk and obesity.

Keywords: PR interval; atrial fibrillation; biomarker; cardiac electrophysiology; molecular epidemiology; risk factors.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Atrial Fibrillation / diagnostic imaging
  • Atrial Fibrillation / genetics
  • Atrial Fibrillation / physiopathology*
  • Body Mass Index
  • Case-Control Studies
  • Electrocardiography*
  • Female
  • Genotype
  • Humans
  • Male
  • Metabolic Syndrome / complications
  • Middle Aged
  • Odds Ratio
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Waist Circumference
  • Young Adult

Grant support