Methylomics of gene expression in human monocytes. Hum Mol Genet

DNAmethylation is one of several epigeneticmechanisms that contribute to the regulation of gene expression; however, the extent to whichmethylation of CpG dinucleotides correlates with gene expression at the genome-wide level is still largely unknown.Using purified primarymonocytes fromsubjects in a large community-based cohort (n 5 1264), we characterizedmethylation (>485 000 CpG sites) andmRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8370 expression phenotypes.We identified 11 203 poten-tial cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a false dis-covery rate threshold of 0.001. Most of the associations were consistent in effect size and direction of effect across sex and three ethnicities. Contrary to expectation, these eMS were not predominately enriched in pro-moter regions, or CpG islands, but rather in the 3 ′ UTR, gene bodies, CpG shores or ‘offshore ’ sites, and both positive and negative correlations between methylation and expression were observed across all locations. eMS were enriched for regions predicted to be regulatory by ENCODE (Encyclopedia of DNA Elements) data in multiple cell types, particularly enhancers. One of the strongest association signals detected (P < 2.2 3 102308) was amethylation probe (cg17005068) in the promoter/enhancer region of the glutathioneS-transferase theta 1 gene (GSTT1, encoding the detoxification enzyme) withGSTT1mRNA expression. Our study provides