Figure 1: Overview of the study design and analytical approach.

We performed an EWAS in 52 MZ twin pairs discordant for T1D in three immune effector cell types: CD4⁺ T cells, CD19⁺ B cells and CD14⁺CD16⁻ monocytes. We used two different approaches to determine differential DNA methylation associated with T1D status in disease-discordant twin pairs. First, we identified DMPs between T1D and healthy co-twins, which correspond to differences in mean DNA methylation levels. Second, we determined DVPs, which reflect heterogeneous ‘epigenetic outliers’ in T1D twins compared with their healthy co-twins. To assess the biological significance of our findings, we analysed three additional, genome-wide DNA methylation data sets in CD14⁺ monocytes and CD4⁺ T cells from 12 T1D-discordant MZ twin pairs; CD14⁺ and CD4⁺ cells from 201 and 139 unrelated, healthy individuals; and cord blood from 98 newborns of whom 50 had progressed to overt T1D during childhood. Finally, we characterized T1D-associated DVPs using cell type-specific gene regulatory circuits. Credits: The immune response, Big Picture (http://bigpictureeducation.com/).