Integration of genetics into a systems model of electrocardiographic traits using humanCVD BeadChip

Gaunt, T.R. et al. (2012) Integration of genetics into a systems model of electrocardiographic traits using humanCVD BeadChip. Circulation: Cardiovascular Genetics, 5(6), pp. 630-638. (doi: 10.1161/CIRCGENETICS.112.962852)

Abstract

<p>Background—Electrocardiographic traits are important, substantially heritable determinants of risk of arrhythmias and sudden cardiac death.</p> <p>Methods and Results—In this study, 3 population-based cohorts (n=10 526) genotyped with the Illumina HumanCVD Beadchip and 4 quantitative electrocardiographic traits (PR interval, QRS axis, QRS duration, and QTc interval) were evaluated for single-nucleotide polymorphism associations. Six gene regions contained single nucleotide polymorphisms associated with these traits at P<10−6, including SCN5A (PR interval and QRS duration), CAV1-CAV2 locus (PR interval), CDKN1A (QRS duration), NOS1AP, KCNH2, and KCNQ1 (QTc interval). Expression quantitative trait loci analyses of top associated single-nucleotide polymorphisms were undertaken in human heart and aortic tissues. NOS1AP, SCN5A, IGFBP3, CYP2C9, and CAV1 showed evidence of differential allelic expression. We modeled the effects of ion channel activity on electrocardiographic parameters, estimating the change in gene expression that would account for our observed associations, thus relating epidemiological observations and expression quantitative trait loci data to a systems model of the ECG.</p> <p>Conclusions—These association results replicate and refine the mapping of previous genome-wide association study findings for electrocardiographic traits, while the expression analysis and modeling approaches offer supporting evidence for a functional role of some of these loci in cardiac excitation/conduction.</p>

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Macfarlane, Professor Peter
• Authors: Gaunt, T.R., Shah, S., Nelson, C.P., Drenos, F., Braund, P.S., Adeniran, I., Folkersen, L., Lawlor, D.A., Casas, J.-P., Amuzu, A., Kivimaki, M., Whittaker, J., Eriksson, P., Zhang, H., Hancox, J.C., Tomaszewski, M., Burton, P.R., Tobin, M.D., Humphries, S.E., Talmud, P.J., Macfarlane, P.W., Hingorani, A.D., Samani, N.J., Kumari, M., and Day, I.N.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Circulation: Cardiovascular Genetics
• Publisher: American Heart Association
• ISSN: 1942-325X
• ISSN (Online): 1942-3268
• Published Online: 08 November 2012
• Copyright Holders: Copyright © 2012 American Heart Association
• First Published: First published in Circulation: Cardiovascular Genetics 5(6):630-638
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher