Abstract
Type 1 diabetes (T1D) is an organ-specific autoimmune disease, whereby immune cell-mediated killing leads to loss of the insulin-producing β cells in the pancreas. Genome-wide association studies (GWAS) have identified over 200 genetic variants associated with risk for T1D. The majority of the GWAS risk variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes substantially contribute to T1D. However, identification of causal regulatory variants associated with T1D risk and their affected genes is challenging due to incomplete knowledge of non-coding regulatory elements and the cellular states and processes in which they function. Here, we performed a comprehensive integrated post-GWAS analysis of T1D to identify functional regulatory variants in enhancers and their cognate target genes. Starting with 1,817 candidate T1D SNPs defined from the GWAS catalog and LDlink databases, we conducted functional annotation analysis using genomic data from various public databases. These include 1) Roadmap Epigenomics, ENCODE, and RegulomeDB for epigenome data; 2) GTEx for tissue-specific gene expression and expression quantitative trait loci data; and 3) lncRNASNP2 for long non-coding RNA data. Our results indicated a prevalent enhancer-based immune dysregulation in T1D pathogenesis. We identified 26 high-probability causal enhancer SNPs associated with T1D, and 64 predicted target genes. The majority of the target genes play major roles in antigen presentation and immune response and are regulated through complex transcriptional regulatory circuits, including those in HLA (6p21) and non-HLA (16p11.2) loci. These candidate causal enhancer SNPs are supported by strong evidence and warrant functional follow-up studies.
Highlights
Type 1 diabetes (T1D) is a chronic autoimmune disease with a T cell-mediated loss of functional pancreatic β-cell mass [1, 2]
We found a total of 85 candidate T1D single nucleotide polymorphism (SNP)-occupied enhancers with effective transcription factors (TFs) binding, and 140 candidate T1D SNPs residing in these enhancers (Fig 1A and S2 Table)
We found that 73 genes are spatially associated with 114 T1D SNPs (S4 Table), among which 24 genes (6 human leukocyte antigen (HLA) and 18 non-HLA genes) overlap with the 159 genes found through the eQTL analysis. 54% (13/24 genes) of the CoDeS3D-identified genes are involved in the immune response
Summary
Type 1 diabetes (T1D) is a chronic autoimmune disease with a T cell-mediated loss of functional pancreatic β-cell mass [1, 2]. Self-reactive T cells are either eliminated by central tolerance induction in the thymus or are controlled by peripheral tolerance mechanisms, including suppression by regulatory T (TREG) cells. Several hypotheses regarding the onset and development of T1D have been suggested. These include the idea that T1D is caused by impaired thymic deletion of autoreactive T cells and/or dysfunctional TREG-mediated suppression of autoreactive T cells [4], or that TREG-resistant hyperactivated effector T cell populations cause T1D by attacking β-cells in the pancreas [5, 6]. At the onset of T1D in non-obese diabetic mice, innate immune cells such as macrophages and dendritic cells infiltrate the islets of Langerhans [7], where they can acquire autoantigens and subsequently stimulate T cell responses [2]
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