Genome- and phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk

Marylyn D. Ritchie, Joshua C. Denny, Rebecca L. Zuvich, Dana C. Crawford, Jonathan S. Schildcrout, Lisa Bastarache, Andrea H. Ramirez, Jonathan D. Mosley, Jill M. Pulley, Melissa A. Basford, Yuki Bradford, Luke V. Rasmussen, Jyotishman Pathak, Christopher G. Chute, Iftikhar J. Kullo, Catherine A. Mccarty, Rex L. Chisholm, Abel N. Kho, Christopher S. Carlson, Eric B. LarsonGail P. Jarvik, Nona Sotoodehnia, Teri A. Manolio, Rongling Li, Daniel R. Masys, Jonathan L. Haines, Dan M. Roden

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

BACKGROUND - ECG QRS duration, a measure of cardiac intraventricular conduction, varies ≈2-fold in individuals without cardiac disease. Slow conduction may promote re-entrant arrhythmias. METHODS AND RESULTS - We performed a genome-wide association study to identify genomic markers of QRS duration in 5272 individuals without cardiac disease selected from electronic medical record algorithms at 5 sites in the Electronic Medical Records and Genomics (eMERGE) network. The most significant loci were evaluated within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium QRS genome-wide association study meta-analysis. Twenty-three single-nucleotide polymorphisms in 5 loci, previously described by CHARGE, were replicated in the eMERGE samples; 18 single-nucleotide polymorphisms were in the chromosome 3 SCN5A and SCN10A loci, where the most significant single-nucleotide polymorphisms were rs1805126 in SCN5A with P=1.2×10 (eMERGE) and P=2.5×10 (CHARGE) and rs6795970 in SCN10A with P=6×10 (eMERGE) and P=5×10 (CHARGE). The other loci were in NFIA, near CDKN1A, and near C6orf204. We then performed phenome-wide association studies on variants in these 5 loci in 13859 European Americans to search for diagnoses associated with these markers. Phenome-wide association study identified atrial fibrillation and cardiac arrhythmias as the most common associated diagnoses with SCN10A and SCN5A variants. SCN10A variants were also associated with subsequent development of atrial fibrillation and arrhythmia in the original 5272 "heart- healthy" study population. CONCLUSIONS - We conclude that DNA biobanks coupled to electronic medical records not only provide a platform for genome-wide association study but also may allow broad interrogation of the longitudinal incidence of disease associated with genetic variants. The phenome-wide association study approach implicated sodium channel variants modulating QRS duration in subjects without cardiac disease as predictors of subsequent arrhythmias.

Original languageEnglish (US)
Pages (from-to)1377-1385
Number of pages9
JournalCirculation
Volume127
Issue number13
DOIs
StatePublished - Apr 2 2013

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Keywords

  • Atrial fibrillation
  • Electronic health records
  • Genetics
  • Genome-wide association study

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Ritchie, M. D., Denny, J. C., Zuvich, R. L., Crawford, D. C., Schildcrout, J. S., Bastarache, L., Ramirez, A. H., Mosley, J. D., Pulley, J. M., Basford, M. A., Bradford, Y., Rasmussen, L. V., Pathak, J., Chute, C. G., Kullo, I. J., Mccarty, C. A., Chisholm, R. L., Kho, A. N., Carlson, C. S., ... Roden, D. M. (2013). Genome- and phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk. Circulation, 127(13), 1377-1385. https://doi.org/10.1161/CIRCULATIONAHA.112.000604