A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation

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.

Single-Cell Multi-Omic Roadmap of Human Fetal Pancreatic Development

“…In contrast to Type 1 Diabetes (T1D) were the majority of genetic association signals exert their effect through the immune system (Kim et al, 2021), there is compelling evidence fromphysiology (De Franco, 2020; Dimas et al, 2014) and epigenomics (Thurner et al, 2018) that pancreatic islets are a key tissue mediating a large proportion of the genetic risk for type 2 diabetes (T2D). T2D is a complex disease with multiple associated genetic risk loci identified through genome-wide association studies (GWAS) have identified >700 signals (Mahajan et al, 2018), the majority of which signals are located in non-coding regions of the genome with a presumed regulatory function (Mahajan et al, 2018).…”

Genetic and Epigenetic Aspects of Type 1 Diabetes Mellitus: Modern View on the Problem

“…In addition, 78 loci were found in 42 genes of long non-coding RNA; 13 of these 78 loci were located in enhancer regions, and among them, rs3129716 and rs886424 were highly likely to be the most significant enhancer SNPs. The authors inferred that most of the identified target genes played an important role in the immune response and regulation of activity of gene expression including HLA genes (6p21) [62].…”

Prediction of Drug Targets for Specific Diseases Leveraging Gene Perturbation Data: A Machine Learning Approach

“…Moreover, another study showed that a risk allele within USF1 appeared to remove the inductive effect of insulin on USF1 expression, which in turn affected the expression of other target genes, contributing to increased risk of cardiometabolic diseases [75]. HLA-DMB was also reported to be associated with type 1 DM in several human genetic studies [76][77][78].…”