Genome- and Phenome-Wide Analyses of Cardiac Conduction Identifies Markers of Arrhythmia Risk
Year: 2013
Type: article
Study design: Observational Study
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(-8) (eMERGE) and P=2.5×10(-20) (CHARGE) and rs6795970 in SCN10A with P=6×10(-6) (eMERGE) and P=5×10(-27) (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.
Source: Circulation
Authors: 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. Larson, Gail P. Jarvik, Nona Sotoodehnia, Teri A. Manolio, Rongling Li, Daniel R. Masys, Jonathan L. Haines, Dan M. Roden
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: American Heart Association, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, U.S. National Library of Medicine, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1569664509, G1800770867, G1875582626, G241213959, G2424387874, G2860569048, G2878691739, G3420921512, G4429312988, G491532010, G556970706, Genetic Discovery and Application in a Clinical Setting Continuing a Partnership, Beyond PheWAS: Recognition of Phenotype Patterns for Discovery and Translation, Delineating epidemiological and genetic factors associated with cardiac diastolic dysfunction, The Vanderbilt Institute for Clinical and Translational Research (VICTR), Clinical Pharmacology Training Program, G906879642, G949362299
OpenAlex ID: W2029119894