Integration of genetics into a systems model of electrocardiographic traits using humancvd beadchip

Gaunt, Tom R, Shah, Sonia, Nelson, Christopher P, Drenos, Fotios, Braund, Peter S., Adeniran, Ismail, Folkersen, Lasse, Lawlor, Debbie A., Casas, Juan-Pablo, Amuzu, Antoinette, Kivimaki, Mika, Whittaker, John, Eriksson, Per, Zhang, Henggui, Hancox, Jules C., Tomaszewski, Maciej, Burton, Paul R., Tobin, Martin D., Humphries, Steve E., Talmud, Philippa J., Macfarlane, Peter W., Hingorani, Aroon D., Samani, Nilesh J., Kumari, Meena and Day, Ian N.M. (2012) Integration of genetics into a systems model of electrocardiographic traits using humancvd beadchip. Circulation: Cardiovascular Genetics, 5 6: 630-638. doi:10.1161/CIRCGENETICS.112.962852

Author Gaunt, Tom R
Shah, Sonia
Nelson, Christopher P
Drenos, Fotios
Braund, Peter S.
Adeniran, Ismail
Folkersen, Lasse
Lawlor, Debbie A.
Casas, Juan-Pablo
Amuzu, Antoinette
Kivimaki, Mika
Whittaker, John
Eriksson, Per
Zhang, Henggui
Hancox, Jules C.
Tomaszewski, Maciej
Burton, Paul R.
Tobin, Martin D.
Humphries, Steve E.
Talmud, Philippa J.
Macfarlane, Peter W.
Hingorani, Aroon D.
Samani, Nilesh J.
Kumari, Meena
Day, Ian N.M.
Title Integration of genetics into a systems model of electrocardiographic traits using humancvd beadchip
Journal name Circulation: Cardiovascular Genetics   Check publisher's open access policy
ISSN 1942-325X
Publication date 2012-12
Year available 2012
Sub-type Article (original research)
DOI 10.1161/CIRCGENETICS.112.962852
Open Access Status
Volume 5
Issue 6
Start page 630
End page 638
Total pages 9
Place of publication New York United States
Publisher Lippincott Williams & Wilkins
Language eng
Subject 2705 Cardiology and Cardiovascular Medicine
2716 Genetics (clinical)
1311 Genetics
Formatted abstract
Background-Electrocardiographic traits are important, substantially heritable determinants of risk of arrhythmias and sudden cardiac death.

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.

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.
Keyword Arrhythmia
Genetic association
QT interval electrocardiography
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 9 times in Thomson Reuters Web of Science Article | Citations
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