van der Harst, P;
van Setten, J;
Verweij, N;
Vogler, G;
Franke, L;
Maurano, MT;
Wang, X;
... de Bakker, PIW; + view all
(2016)
52 Genetic Loci Influencing Myocardial Mass.
Journal of the American College of Cardiology
, 68
(13)
pp. 1435-1448.
10.1016/j.jacc.2016.07.729.
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Abstract
BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10−8. These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
| Type: | Article |
|---|---|
| Title: | 52 Genetic Loci Influencing Myocardial Mass |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jacc.2016.07.729 |
| Publisher version: | http://dx.doi.org/10.1016/j.jacc.2016.07.729 |
| Language: | English |
| Additional information: | © 2016 the authors. Published by elsevier on behalf of the american College of cardiology fo undation. This is an open access article under The cc by-nc-nd license ( http://creativecommons.O rg/licenses/by-nc-nd/4.0/ ). |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Cardiovascular System & Cardiology, electrocardiogram, genetic association study, heart failure, left ventricular hypertrophy, QRS, LEFT-VENTRICULAR HYPERTROPHY, CARDIAC-HYPERTROPHY, REGULATORY DNA, ELECTROCARDIOGRAM, MORTALITY, DISEASE, VOLTAGE, DYSFUNCTION, GENOME, HEART |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1523921 |
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