Type 1 diabetes mellitus-associated genetic variants contribute to overlapping immune regulatory networks

Abstract

Type 1 diabetes (T1D) is a chronic metabolic disorder characterised by the autoimmune destruction of insulin-producing pancreatic islet 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 predisposition to T1D. There is increasing evidence that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue-and development-specific manner. Here, we used three-dimensional (3D) genome organization data to identify genes that physically co-localized with DNA regions that contained T1D-associated SNPs in the nucleus. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression database identified a subset of SNPs that significantly affected gene expression. We identified 298 spatially regulated genes including HLA-DRB1, LAT, MICA, BTN3A2, CTLA4, CD226, NOTCH1, TRIM26, CLEC2B, TYK2, and FLRT3, which exhibit tissue-specific effects in multiple tissues. We observed that the T1D-associated variants interconnect through networks that form part of the immune regulatory pathways, including immune-cell activation, cytokine signalling, and programmed cell death protein-1 (PD-1). These pathways have been implicated in the pancreatic beta-cell inflammation and destruction as observed in T1D. Our results demonstrate that T1D-associated variants contribute to adaptive immune signalling, and immune-cell proliferation and activation through tissue and cell-type specific regulatory networks.\n\nAuthor SummaryAlthough genome-wide association studies have identified risk regions across the human genome that predispose individuals to the development of type 1 diabetes (T1D), the mechanisms through which these regions contribute to disease is unclear. Here, we used population-based genetic data from genome-wide association studies (GWAS) to understand how the three-dimensional (3D) organization of the DNA contributes to the differential expression of genes involved in immune system dysregulation as observed in T1D. We identified interconnected regulatory networks that affect immune pathways (adaptive immune signalling and immune-cell proliferation and activation) in a tissue and cell-type specific manner. Some of these pathways are implicated in the pancreatic beta-cell destruction. However, we observed other regulatory changes in tissues that are not typically considered to be central to the pathology of T1D, which represents a novel insight into the disease. Collectively, our data represent a novel resource for the hypothesis-driven development of diagnostic, prognostic and therapeutic interventions in T1D.