Hemerich, D;
Pei, J;
Harakalova, M;
van Setten, J;
Boymans, S;
Boukens, BJ;
Efimov, IR;
... Asselbergs, FW; + view all
(2019)
Integrative Functional Annotation of 52 Genetic Loci Influencing Myocardial Mass Identifies Candidate Regulatory Variants and Target Genes.
Circulation: Genomic and Precision Medicine
, 12
(2)
pp. 76-83.
10.1161/CIRCGEN.118.002328.
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Abstract
BACKGROUND: Regulatory elements may be involved in the mechanisms by which 52 loci influence myocardial mass, reflected by abnormal amplitude and duration of the QRS complex on the ECG. Functional annotation thus far did not take into account how these elements are affected in disease context. METHODS: We generated maps of regulatory elements on hypertrophic cardiomyopathy patients (ChIP-seq N=14 and RNA-seq N=11) and nondiseased hearts (ChIP-seq N=4 and RNA-seq N=11). We tested enrichment of QRS-associated loci on elements differentially acetylated and directly regulating differentially expressed genes between hypertrophic cardiomyopathy patients and controls. We further performed functional annotation on QRS-associated loci using these maps of differentially active regulatory elements. RESULTS: Regions differentially affected in disease showed a stronger enrichment ( P=8.6×10-5) for QRS-associated variants than those not showing differential activity ( P=0.01). Promoters of genes differentially regulated between hypertrophic cardiomyopathy patients and controls showed more enrichment ( P=0.001) than differentially acetylated enhancers ( P=0.8) and super-enhancers ( P=0.025). We also identified 74 potential causal variants overlapping these differential regulatory elements. Eighteen of the genes mapped confirmed previous findings, now also pinpointing the potentially affected regulatory elements and candidate causal variants. Fourteen new genes were also mapped. CONCLUSIONS: Our results suggest differentially active regulatory elements between hypertrophic cardiomyopathy patients and controls can offer more insights into the mechanisms of QRS-associated loci than elements not affected by disease.
| Type: | Article |
|---|---|
| Title: | Integrative Functional Annotation of 52 Genetic Loci Influencing Myocardial Mass Identifies Candidate Regulatory Variants and Target Genes |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1161/CIRCGEN.118.002328 |
| Publisher version: | https://doi.org/10.1161/CIRCGEN.118.002328 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | electrocardiography, genetics, cardiomyopathies, heart failure, acetylation |
| 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 |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10071121 |
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