Characterization of the genetic determinants of context-specific DNA methylation in primary monocytes

To better understand inter-individual variation in sensitivity of DNA methylation (DNAm) to immune activity, we characterized effects of inflammatory stimuli on primary monocyte DNAm (n = 190). We find that monocyte DNAm is site-dependently sensitive to lipopolysaccharide (LPS), with LPS-induced demethylation occurring following hydroxymethylation. We identify 7,359 high-confidence immune-modulated CpGs (imCpGs) that differ in genomic localization and transcription factor usage according to whether they represent a gain or loss in DNAm. Demethylated imCpGs are profoundly enriched for enhancers and colocalize to genes enriched for disease associations, especially cancer. DNAm is age associated, and we find that 24-h LPS exposure triggers approximately 6 months of gain in epigenetic age, directly linking epigenetic aging with innate immune activity. By integrating LPS-induced changes in DNAm with genetic variation, we identify 234 imCpGs under local genetic control. Exploring shared causal loci between LPS-induced DNAm responses and human disease traits highlights examples of disease-associated loci that modulate imCpG formation. [Display omitted] •LPS stimulation causes widespread DNA methylation changes in primary monocytes•Loci demethylated by LPS are enriched for enhancers and genes implicated in cancer•Innate immune activation in monocytes induces epigenetic aging•Shaping of DNA methylation by LPS is under genetic control To explore the relationship between immune activity, genetic variation, and DNA methylation (DNAm), Gilchrist et al. characterized consequences of inflammatory stimuli on monocyte DNAm (n = 190 paired samples). They find that monocyte DNAm shows stimulus-specific focal sensitivity at sites enriched for enhancers, is influenced by genotype, and predominantly involves cancer mutated genes.