Enrichment of Spatial eGenes Colocalized with Type 2 Diabetes Mellitus Genome-Wide Association Study Signals in the Lysosomal Pathway

Abstract

Genome-wide association studies (GWAS) have identified genetic markers associated with type 2 diabetes mellitus (T2DM). Additionally, tissue-specific expression quantitative trait loci (eQTL) studies have revealed regulatory elements influencing gene expression in specific tissues. We performed enrichment analyses using spatial eGenes corresponding to known T2DM GWAS signals to uncover T2DM pathological pathways. T2DM GWAS signals were obtained from the GWAS Catalog, and spatial eQTL data from T2DM-associated tissues, including visceral adipose tissue, liver, skeletal muscle, and pancreas, were sourced from the Genotype-Tissue Expression Consortium. The eGenes were enriched in Kyoto Encyclopedia of Genes and Genomes biological pathways using the Benjamini–Hochberg method. Colocalization analysis of 2857 independent T2DM GWAS signals identified 556 eGenes in visceral adipose tissue, 176 in liver, 715 in skeletal muscle, and 384 in pancreas (PFDR < 0.05 where PFDR is the false discovery rate). These eGenes showed enrichment in various pathways (PBH < 0.05 where PBH is the corrected P for the Benjamini–Hochberg multiple testing), especially the lysosomal pathway in pancreatic tissue. Unlike the mTOR pathway in T2DM autophagy dysregulation, the role of lysosomes remains poorly understood. The enrichment analysis of spatial eGenes associated with T2DM GWAS signals highlights the importance of the lysosomal pathway in autophagic termination. Thus, investigating the processes involving autophagic termination associated with lysosomes is a priority for understanding T2DM pathogenesis.

Genetic Association of Diagnostic Traits of Metabolic Syndrome with Lysosomal Pathways: Insights from Target Gene Enrichment Analysis

“…Lysosomes are involved in insulin secretion and glucose homeostasis by maintaining the health of pancreatic β-cells [46]. This lysosomal signaling function in insulin secretion and insulin resistance was supported by a recent study in which spatial eGenes colocalized with type 2 diabetes GWAS signals were enriched in the lysosomal pathway [29]. Enrichment analysis for GM in the current study also suggests a potential role of lysosomes in insulin secretion/resistance.…”

“…We used the false discovery rate (P FDR ) to determine the statistical significance of colocalization for each tissue, with a significance threshold of P FDR = 0.05. The enrichment analysis excluded eGenes within the major histocompatibility complex (MHC) region because strong linkages in a broad region may lead to spurious enrichment [29].…”