Epigenome-wide association study for dilated cardiomyopathy in left ventricular heart tissue identifies putative gene sets associated with cardiac development and early indicators of cardiac risk

Abstract

BackgroundMethylation changes linked to dilated cardiomyopathy (DCM) affect cardiac gene expression. We investigate DCM mechanisms regulated by CpG methylation using multi-omics and causal analyses in the largest cohort of left ventricular tissues available. MethodsWe mapped DNA methylation at [~]850,000 CpG sites, performed array-based genotyping and RNA sequencing in left-ventricular tissue samples from failing and non-failing hearts across two independent DCM cohorts (discovery n=329, replication n=85). Summary data-based Mendelian Randomization (SMR) was applied to explore the causal contribution of sentinel CpGs to DCM. Fine-mapping of regions surrounding sentinel CpGs revealed additional signals for cardiovascular disease risk factors. Coordinated changes across multiple CpG sites were examined using weighted gene correlation network analysis (WGCNA). ResultsWe identified 194 epigenome-wide significant CpGs associated with DCM (discovery P<5.96E-08), enriched in active chromatin states in heart tissue. Amongst these, 183 sentinel CpGs significantly influenced the expression of 849 proximal genes ({+/-}1Mb). SMR suggested the causal contribution of two sentinel CpGs to DCM and 36 sentinel CpGs to the expression of 43 unique proximal genes (P<0.05). Colocalization analyses indicated that a single causal variant may underlie the methylation-gene expression relationship for three sentinel CpGs. Fine-mapping revealed additional signals linked to cardiovascular traits including hsCRP and blood pressure. Co-methylation modules were enriched in genes related to cardiac physiological and pathological processes and their corresponding transcriptional regulators. ConclusionsUsing the largest series of left ventricular tissue to date, this study investigates the causal role of cardiac methylation changes in DCM and suggests targets for experimental studies to probe DCM pathogenesis.