Genome- and Phenome-Wide Analyses of Cardiac Conduction Identifies Markers of Arrhythmia Risk
ECG QRS duration, a measure of cardiac intraventricular conduction, varies ≈2-fold in individuals without cardiac disease. Slow conduction may promote re-entrant arrhythmias. We performed a genome-wide association study to identify genomic markers of QRS duration in 5272 individuals without cardiac...
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| Published in | Circulation (New York, N.Y.) Vol. 127; no. 13; pp. 1377 - 1385 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Hagerstown, MD
Lippincott Williams & Wilkins
02.04.2013
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0009-7322 1524-4539 1524-4539 |
| DOI | 10.1161/CIRCULATIONAHA.112.000604 |
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| Abstract | ECG QRS duration, a measure of cardiac intraventricular conduction, varies ≈2-fold in individuals without cardiac disease. Slow conduction may promote re-entrant arrhythmias.
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.
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. |
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| AbstractList | ECG QRS duration, a measure of cardiac intraventricular conduction, varies ≈2-fold in individuals without cardiac disease. Slow conduction may promote re-entrant arrhythmias.
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.
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. ECG QRS duration, a measure of cardiac intraventricular conduction, varies ≈2-fold in individuals without cardiac disease. Slow conduction may promote re-entrant arrhythmias.BACKGROUNDECG QRS duration, a measure of cardiac intraventricular conduction, varies ≈2-fold in individuals without cardiac disease. Slow conduction may promote re-entrant arrhythmias.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.METHODS AND RESULTSWe 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.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.CONCLUSIONSWe 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. |
| Author | Larson, Eric B. Jarvik, Gail P. Pathak, Jyotishman Masys, Daniel R. McCarty, Catherine A. Chisholm, Rex L. Bradford, Yuki Roden, Dan M. Bastarache, Lisa Sotoodehnia, Nona Rasmussen, Luke V. Crawford, Dana C. Li, Rongling Pulley, Jill M. Carlson, Christopher S. Chute, Christopher G. Manolio, Teri A. Ritchie, Marylyn D. Denny, Joshua C. Haines, Jonathan L. Basford, Melissa A. Mosley, Jonathan D. Kho, Abel N. Zuvich, Rebecca L. Schildcrout, Jonathan S. Ramirez, Andrea H. Kullo, Iftikhar J. |
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Essentia Institute of – sequence: 17 givenname: Rex L. surname: Chisholm fullname: Chisholm, Rex L. organization: From Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park (M.D.R.); Departments of Biomedical Informatics (J.C.D., L.B.), Medicine (J.C.D., A.H.R., J.D.M., D.M.R.), Molecular Physiology and Biophysics (R.L.Z., D.C.C., J.L.H.), and Pharmacology (D.M.R.), Center for Human Genetics Research (D.C.C., Y.B., J.L.H.), Biostatistics (J.S.S.), and Office of Research (J.M.P., M.A.B.), Vanderbilt University School of Medicine, Nashville, TN; Essentia Institute of – sequence: 18 givenname: Abel N. surname: Kho fullname: Kho, Abel N. organization: From Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park (M.D.R.); Departments of Biomedical Informatics (J.C.D., L.B.), Medicine (J.C.D., A.H.R., J.D.M., D.M.R.), Molecular Physiology and Biophysics (R.L.Z., D.C.C., J.L.H.), and Pharmacology (D.M.R.), Center for Human Genetics Research (D.C.C., Y.B., J.L.H.), Biostatistics (J.S.S.), and Office of Research (J.M.P., M.A.B.), Vanderbilt University School of Medicine, Nashville, TN; Essentia Institute of – sequence: 19 givenname: Christopher S. surname: Carlson fullname: Carlson, Christopher S. organization: From Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park (M.D.R.); Departments of Biomedical Informatics (J.C.D., L.B.), Medicine (J.C.D., A.H.R., J.D.M., D.M.R.), Molecular Physiology and Biophysics (R.L.Z., D.C.C., J.L.H.), and Pharmacology (D.M.R.), Center for Human Genetics Research (D.C.C., Y.B., J.L.H.), Biostatistics (J.S.S.), and Office of Research (J.M.P., M.A.B.), Vanderbilt University School of Medicine, Nashville, TN; Essentia Institute of – sequence: 20 givenname: Eric B. surname: Larson fullname: Larson, Eric B. organization: From Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park (M.D.R.); Departments of Biomedical Informatics (J.C.D., L.B.), Medicine (J.C.D., A.H.R., J.D.M., D.M.R.), Molecular Physiology and Biophysics (R.L.Z., D.C.C., J.L.H.), and Pharmacology (D.M.R.), Center for Human Genetics Research (D.C.C., Y.B., J.L.H.), Biostatistics (J.S.S.), and Office of Research (J.M.P., M.A.B.), Vanderbilt University School of Medicine, Nashville, TN; 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Essentia Institute of – sequence: 23 givenname: Teri A. surname: Manolio fullname: Manolio, Teri A. organization: From Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park (M.D.R.); Departments of Biomedical Informatics (J.C.D., L.B.), Medicine (J.C.D., A.H.R., J.D.M., D.M.R.), Molecular Physiology and Biophysics (R.L.Z., D.C.C., J.L.H.), and Pharmacology (D.M.R.), Center for Human Genetics Research (D.C.C., Y.B., J.L.H.), Biostatistics (J.S.S.), and Office of Research (J.M.P., M.A.B.), Vanderbilt University School of Medicine, Nashville, TN; Essentia Institute of – sequence: 24 givenname: Rongling surname: Li fullname: Li, Rongling organization: From Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park (M.D.R.); Departments of Biomedical Informatics (J.C.D., L.B.), Medicine (J.C.D., A.H.R., J.D.M., D.M.R.), Molecular Physiology and Biophysics (R.L.Z., D.C.C., J.L.H.), and Pharmacology (D.M.R.), Center for Human Genetics Research (D.C.C., Y.B., J.L.H.), Biostatistics (J.S.S.), and Office of Research (J.M.P., M.A.B.), Vanderbilt University School of Medicine, Nashville, TN; Essentia Institute of – sequence: 25 givenname: Daniel R. surname: Masys fullname: Masys, Daniel R. organization: From Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park (M.D.R.); Departments of Biomedical Informatics (J.C.D., L.B.), Medicine (J.C.D., A.H.R., J.D.M., D.M.R.), Molecular Physiology and Biophysics (R.L.Z., D.C.C., J.L.H.), and Pharmacology (D.M.R.), Center for Human Genetics Research (D.C.C., Y.B., J.L.H.), Biostatistics (J.S.S.), and Office of Research (J.M.P., M.A.B.), Vanderbilt University School of Medicine, Nashville, TN; Essentia Institute of – sequence: 26 givenname: Jonathan L. surname: Haines fullname: Haines, Jonathan L. organization: From Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park (M.D.R.); Departments of Biomedical Informatics (J.C.D., L.B.), Medicine (J.C.D., A.H.R., J.D.M., D.M.R.), Molecular Physiology and Biophysics (R.L.Z., D.C.C., J.L.H.), and Pharmacology (D.M.R.), Center for Human Genetics Research (D.C.C., Y.B., J.L.H.), Biostatistics (J.S.S.), and Office of Research (J.M.P., M.A.B.), Vanderbilt University School of Medicine, Nashville, TN; Essentia Institute of – sequence: 27 givenname: Dan M. surname: Roden fullname: Roden, Dan M. organization: From Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park (M.D.R.); Departments of Biomedical Informatics (J.C.D., L.B.), Medicine (J.C.D., A.H.R., J.D.M., D.M.R.), Molecular Physiology and Biophysics (R.L.Z., D.C.C., J.L.H.), and Pharmacology (D.M.R.), Center for Human Genetics Research (D.C.C., Y.B., J.L.H.), Biostatistics (J.S.S.), and Office of Research (J.M.P., M.A.B.), Vanderbilt University School of Medicine, Nashville, TN; Essentia Institute of |
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| Snippet | ECG QRS duration, a measure of cardiac intraventricular conduction, varies ≈2-fold in individuals without cardiac disease. Slow conduction may promote... |
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| SubjectTerms | Adult Aged Aged, 80 and over Arrhythmias, Cardiac - diagnosis Arrhythmias, Cardiac - epidemiology Arrhythmias, Cardiac - genetics Biological and medical sciences Blood and lymphatic vessels Cardiac dysrhythmias Cardiology. Vascular system Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Female Genetic Markers - genetics Genome-Wide Association Study - methods Heart Heart Conduction System - metabolism Heart Conduction System - physiopathology Heart Rate - genetics Humans Male Medical sciences Middle Aged Phenotype Polymorphism, Single Nucleotide - genetics Risk Factors |
| Title | Genome- and Phenome-Wide Analyses of Cardiac Conduction Identifies Markers of Arrhythmia Risk |
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