Integrative Functional Annotation of 52 Genetic Loci Influencing Myocardial Mass Identifies Candidate Regulatory Variants and Target Genes

Daiane Hemerich, Jiayi Pei, Magdalena Harakalova, Jessica van Setten, Sander Boymans, Bas J Boukens, Igor R Efimov, Michelle Michels, Jolanda van der Velden, Aryan Vink, Caroline Cheng, Pim van der Harst, Jason H Moore, Michal Mokry, Vinicius Tragante, Folkert W Asselbergs

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article numbere002328
Pages (from-to)76-83
Number of pages8
JournalCirculation. Genomic and precision medicine
Volume12
Issue number2
Early online date25 Jan 2019
DOIs
Publication statusPublished - 1 Feb 2019

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