Identification of loci where DNA methylation potentially mediates genetic risk of type 1 diabetes

Background: The risk of Type 1 Diabetes (T1D) comprises genetic and environmental components, which both could be mediated by DNA methylation (DNAm). Previous studies established associations between DNAm and T1D GWAS variants, but it is unclear whether these associations indicate causation or were raised due to confounding factors or even reverse causation, i.e. whether causal variants first introduce gene expression changes which in turn cause DNAm changes and not the other way around. We systematically investigated the causal roles of DNAm in mediating common genetic risk of T1D in a large-scale population sampled longitudinally.

Methods: We first assessed whether DNAm and T1D share a common genetic influence at genome-wide scale by performing an enrichment analysis using summary statistics. Subsequently, at T1D loci we regressed 65 top GWAS nucleotide polymorphisms (SNPs) with Illumina 450k MethylationBeadChip data in the ARIES cohort where blood DNAm were measured at birth (n=844), childhood (n=846) and adolescence (n=907). Next, joint likelihood mapping was performed to identify loci where the causal variants for DNAm and T1D were shared. At these loci bi-directional two-sample Mendelian Randomization was used to assess the causal roles of DNAm. Finally, we investigated whether DNAm influence local gene expression using whole blood data from the GTEx consortium.

Results: There was a common genetic influence for both DNAm and T1D across the genome, implying that DNAm could be either on the causal pathway to T1D or a non-causal biomarker of T1D genetic risk. We found 159 proximal SNP-cytosine phosphate guanine (CpG) pairs (cis), and 7 distal SNP-CpG associations (trans) at birth, childhood, and adolescence, but DNAm did not play causal roles at most of these loci. At 5 loci, ITGB3BP, AFF3, PTPN2, CTSH and CTLA4, DNAm is potentially mediating the genetic risk of T1D mainly by influencing local gene expression.