DNA Methylation Near DLGAP2 May Mediate the Relationship between Family History of Type 1 Diabetes and Type 1 Diabetes Risk

Figure 1

Mediation conceptual model and analytical approach. The directed acyclic graph shows the hypothesized relationships between family history of T1D (exposure), DNA methylation (mediator), and risk of T1D (outcome). Colors of the arrows represent the indirect (pink) and direct (tan) mediation effects. We implemented three models to first summarize longitudinal DNA methylation over time and then combined results from the mediator and outcome models in a counterfactual framework to estimate the causal indirect and direct effects. To accommodate possible interaction between the family history of T1D and DNA methylation, the outcome model includes an interaction term, and indirect and direct effects are reported separately for subjects with affected mothers and subjects with affected fathers or siblings, both compared to subjects with no family history of T1D.