Epigenome-wide association study of DNA methylation and adult asthma in the agricultural lung health study

Epigenome-wide studies of methylation in children support a role for epigenetic mechanisms in asthma. Studies in adults are rare, and few have examined non-atopic asthma. We conducted the largest epigenome-wide association study of blood DNA methylation in adults in relation to non-atopic and atopic asthma.We measured DNA methylation in blood using the Illumina MethylationEPIC array among 2286 participants in a case-control study of current adult asthma nested within a U.S. agricultural cohort. Atopy was defined by serum specific immunoglobulin E. Participants were categorised as atopy without asthma (n=185), non-atopic asthma (n=673), atopic asthma (n=271), or a reference group of neither atopy nor asthma (n=1157). Analyses were conducted using logistic regression.No associations were observed with atopy without asthma. Numerous CpGs were differentially methylated in non-atopic asthma (8 at family-wise error rate [FWER] p<9x10(-8); 524 at False Discovery Rate [FDR]<0.05) and implicated 382 novel genes. More CpGs were identified in atopic asthma (181 at FWER; 1086 at FDR) and implicated 569 novel genes. 104 FDR CpGs overlapped. 35% of CpGs in non-atopic asthma and 91% in atopic asthma replicated in studies of whole blood, eosinophils, airway epithelium, or nasal epithelium. Implicated genes were enriched in pathways related to the nervous system or inflammation.We identified numerous, distinct differentially methylated CpGs in non-atopic and atopic asthma. Many CpGs from blood replicated in asthma-relevant tissues. These circulating biomarkers reflect risk and sequelae of disease and implicate novel genes associated with non-atopic and atopic asthma.