Investigating the Genetic Architecture of the PR Interval Using Clinical Phenotypes

Jonathan D. Mosley*, M. Benjamin Shoemaker, Quinn S. Wells, Dawood Darbar, Christian M. Shaffer, Todd L. Edwards, Lisa Bastarache, Catherine A. McCarty, Will Thompson, Christopher G. Chute, Gail P. Jarvik, David R. Crosslin, Eric B. Larson, Iftikhar J. Kullo, Jennifer A. Pacheco, Peggy L. Peissig, Murray H. Brilliant, James G. Linneman, John S. Witte, Josh C. DennyDan M. Roden

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Article numbere001482
JournalCirculation: Cardiovascular Genetics
Volume10
Issue number2
DOIs
StatePublished - Apr 1 2017

Keywords

  • PR interval
  • atrial fibrillation
  • biomarker
  • cardiac electrophysiology
  • molecular epidemiology
  • risk factors

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

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  • Cite this

    Mosley, J. D., Shoemaker, M. B., Wells, Q. S., Darbar, D., Shaffer, C. M., Edwards, T. L., Bastarache, L., McCarty, C. A., Thompson, W., Chute, C. G., Jarvik, G. P., Crosslin, D. R., Larson, E. B., Kullo, I. J., Pacheco, J. A., Peissig, P. L., Brilliant, M. H., Linneman, J. G., Witte, J. S., ... Roden, D. M. (2017). Investigating the Genetic Architecture of the PR Interval Using Clinical Phenotypes. Circulation: Cardiovascular Genetics, 10(2), [e001482]. https://doi.org/10.1161/CIRCGENETICS.116.001482