New Insights Into Mitochondrial Dysfunction at Disease Susceptibility Loci in the Development of Type 2 Diabetes

Abstract

This study investigated the potential genetic mechanisms which underlie adipose tissue mitochondrial dysfunction in Type 2 diabetes (T2D), by systematically identifying nuclear-encoded mitochondrial genes (NEMGs) among the genes regulated by T2D-associated genetic loci. The target genes of these ‘disease loci’ were identified by mapping genetic loci associated with both disease and gene expression levels (expression quantitative trait loci, eQTL) using high resolution genetic maps, with independent estimates co-locating to within a small genetic distance. These co-locating signals were defined as T2D-eQTL and the target genes as T2D cis-genes. In total, 763 cis-genes were associated with T2D-eQTL, of which 50 were NEMGs. Independent gene expression datasets for T2D and insulin resistant cases and controls confirmed that the cis-genes and cis-NEMGs were enriched for differential expression in cases, providing independent validation that genetic maps can identify informative functional genes. Two additional results were consistent with a potential role of T2D-eQTL in regulating the 50 identified cis-NEMGs in the context of T2D risk: (1) the 50 cis-NEMGs showed greater differential expression compared to other NEMGs and (2) other NEMGs showed a trend towards significantly decreased expression if their expression levels correlated more highly with the subset of 50 cis-NEMGs. These 50 cis-NEMGs, which are differentially expressed and associated with mapped T2D disease loci, encode proteins acting within key mitochondrial pathways, including some of current therapeutic interest such as the metabolism of branched-chain amino acids, GABA and biotin.

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

“…This study suggests a hypothesis that glutathione deficiency may contribute to misfolded proinsulin, leading to apoptosis of pancreatic beta cells. Other tissue-specific eQTL studies have indicated additional etiological factors in T2DM, such as metabolic stress-induced beta cell dysfunction [12] and mitochondrial dysfunction in adipose tissue [13]. The objective of this study was to identify spatial eGenes associated with T2DM GWAS signals and conduct enrichment analysis on these eGenes to uncover pathological pathways potentially contributing to the development of T2DM.…”