Integration of Genetics into a Systems Model of Electrocardiographic Traits using HumanCVD BeadChip

Tom R Gaunt, Sonia Shah, Christopher P Nelson, Fotios Drenos, Peter S Braund, Ismail Adeniran, Lasse Folkersen, Debbie A Lawlor, Juan-Pablo Casas, Antoinette Amuzu, Mika Kivimaki, John Whittaker, Per Eriksson, Henggui Zhang, Jules C Hancox, Maciej Tomaszewski, Paul R Burton, Martin D Tobin, Steve E Humphries, Philippa J TalmudPeter W Macfarlane, Aroon D Hingorani, Nilesh J Samani, Meena Kumari, Ian N M Day

Research output: Contribution to journalArticle (Academic Journal)

10 Citations (Scopus)

Abstract

BACKGROUND: -Electrocardiographic (ECG) traits are important, substantially heritable, determinants of risk of arrhythmias and sudden cardiac death. METHODS AND RESULTS: -In this study, three population-based cohorts (n=10,526) genotyped with the Illumina HumanCVD Beadchip and four quantitative ECG traits (PR interval, QRS axis, QRS duration and QTc interval) were evaluated for single nucleotide polymorphism (SNP) associations. Six gene regions contained SNPs 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 QTL analyses of top associated SNPs were undertaken in human heart and aortic tissues. NOS1AP, SCN5A, IGFBP3, CYP2C9 and CAV1 showed evidence of differential allelic expression. We modelled the effects of ion channel activity on ECG parameters, estimating the change in gene expression that would account for our observed associations, thus relating epidemiological observations and eQTL data to a systems model of the ECG. CONCLUSIONS: -These association results replicate and refine the mapping of previous genome-wide association study (GWAS) findings for ECG traits, whilst the expression analysis and modelling approaches offer supporting evidence for a functional role of some of these loci in cardiac excitation/conduction.
Original languageEnglish
Pages (from-to)630-638
JournalCirculation: Cardiovascular Genetics
Volume5
Issue number6
DOIs
Publication statusPublished - Dec 2012

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    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., ... Day, I. N. M. (2012). Integration of Genetics into a Systems Model of Electrocardiographic Traits using HumanCVD BeadChip. Circulation: Cardiovascular Genetics, 5(6), 630-638. https://doi.org/10.1161/CIRCGENETICS.112.962852