Integrative analysis of super enhancer SNPs for type 2 diabetes

Abstract

Clinical studies in type 2 diabetes (T2D) primarily focused on the single nucleotide polymorphisms (SNPs) located in protein-coding regions. Recently, the SNPs located in noncoding regions have also been recognized to play an important role in disease susceptibility. The super enhancer is a cluster of transcriptional enhancers located in noncoding regions. It plays a critical role in cell-type specific gene expression. However, the exact mechanism of the super enhancer SNPs for T2D remains unclear. In this study, we integrated genome-wide association studies (GWASs) and T2D cell/tissue-specific histone modification ChIP-seq data to identify T2D-associated SNPs in super enhancer, followed by comprehensive bioinformatics analyses to further explore the functional importance of these SNPs. We identified several interesting T2D super enhancer SNPs. Interesting, most of them were clustered within the same or neighboring super enhancers. A number of SNPs are involved in chromatin interactive regulation and/or potentially influence the binding affinity of transcription factors. Gene Ontology (GO) analysis showed a significant enrichment in several well-known signaling pathways and regulatory process, e.g. WNT signaling pathway, which plays a key role in T2D metabolism. Our results highlighted the potential functional importance of T2D super enhancer SNPs, which may yield novel insights into the pathogenesis of T2D.

Fig 1. Distribution of T2D super enhancer SNPs in human genome.

T2D super enhancer SNPs were annotated to the human genome assembly GRCH37 (hg19). The enrichment of T2D super enhancer SNPs was observed on chromosome 2p21 (THADA), 3q21.1 (ADCY5), 4p16.1 (WFS1) and 10q25.2 (TCF7L2).

Fig 2. Magnified transcription factors enrichment plot for T2D super enhancer SNPs.

Transcription factors are sorted based on their enrichment.

Fig 3. The circle plot of GWAS3D for T2D super enhancer SNPs.

The annotation based on all cell line and CEU population. The red line indicated long-range interaction signals, and the intensity of interaction was represented by the width of the line. Interactive elements with significant SNP will start with ‘I_’.

Fig 4. A functional protein-protein interaction network for T2D super enhancer SNPs target genes.

Connections are based on co-expression and experimental evidence with a STRING v10.0 summary score above 0.4. Each filled node denotes a gene; edges between nodes indicate protein-protein interactions between protein products of the corresponding genes. Different edge colors represent the types of evidence for the association.