Abstract
The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.
Highlights
The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development
In 52 T1D-discordant MZ twin pairs, we isolated three immune effector cell types that play a pivotal role in T1D pathobiology: CD4 þ T cells, CD19 þ B cells and CD14 þ CD16 À monocytes[1]
We found that T1D-associated differentially variable CpG positions (DVPs) (FDRo0.001) were depleted at meQTLs compared with random sets of CpG sites in all three cell types
Summary
The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. The increasing rate of T1D, along with disease discordance in monozygotic (MZ) twins, suggest that non-genetic factors play a major role[3,4]. Such factors, including viral and bacterial infections, diet, and potentially epigenetic and stochastic events, may affect disease predisposition either in utero or in early childhood when predictive autoantibodies emerge[3]. CpG sites are associated with disease status, and differences in DNA methylation levels between cases and controls are recorded[7,8]. The difference in mean DNA methylation at these CpGs is often small (o5%), raising challenges to their biological interpretation
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