Accounting for this interaction, we found that the increased risk of T1D for children with affected mothers compared to those with no family history was mediated through differences in methylation at two CpGs (cg27351978, cg00565786) in the DLGAP2 region, as demonstrated by a significant pure natural indirect effect (odds ratio (OR) = 1.98, 95% confidence interval (CI): 1.06–3.71) and nonsignificant total natural direct effect (OR = 1.65, 95% CI: 0.16–16.62) (for cg00565786). The gene discussed is DLGAP2; the disease is type 1 diabetes mellitus.