Type 1 diabetes (T1D) is a chronic metabolic disorder characterised by the autoimmune destruction of insulin-producing pancreatic beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk loci across the human genome, marked by single nucleotide polymorphisms (SNPs), which confer genetic susceptibility to T1D. Evidence indicates that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue- and developmental-specific manner.
We sought to elucidate the mechanisms through which population-based genetic variants (SNPs) identified from GWAS and prospective studies on T1D contribute to the disease development by identifying the genes regulated by these variants.
We utilised data derived from three-dimensional (3D) genome mapping to identify genes that physically co-localize with DNA regions that are marked by T1D-associated SNPs. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression (GTEx) database identified a subset of SNPs that significantly affected levels of gene expression in human tissues.
We observed that T1D-associated SNPs are associated with the differential expression of genes including HLA-DQB2, TAP2, BTN3A2, CTLA4, RPS26, NOTCH4, IGF2-AS, and long non-coding RNA RP11-973H7.1, which exhibit age- and tissue-specific effects in tissues including the spleen and pancreas. Furthermore, the spatially regulated genes are enriched for immune regulatory pathways that involve antigen presentation, immune cell activation, and cytokine signalling.
Our results demonstrate that T1D-associated genetic variants contribute to adaptive immune regulatory pathways and emphasize the importance of early life events in new-borns at genetic risk of developing autoimmunity and T1D.