Maude, Hannah;
Lau, Winston;
Maniatis, Nikolas;
Andrew, Toby;
(2021)
New Insights Into Mitochondrial Dysfunction at Disease Susceptibility Loci in the Development of Type 2 Diabetes.
Frontiers in Endocrinology
, 12
, Article 694893. 10.3389/fendo.2021.694893.
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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.
| Type: | Article |
|---|---|
| Title: | New Insights Into Mitochondrial Dysfunction at Disease Susceptibility Loci in the Development of Type 2 Diabetes |
| Location: | Switzerland |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fendo.2021.694893 |
| Publisher version: | https://doi.org/10.3389/fendo.2021.694893 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Endocrinology & Metabolism, mitochondrial dysfunction, type 2 diabetes, insulin action and resistance, adipose tissue, gene set enrichment analyses, differential gene expression, heritable susceptibility, INDUCED INSULIN-RESISTANCE, GENE-EXPRESSION OMNIBUS, SET ENRICHMENT ANALYSIS, AFRICAN-AMERICANS, MUSCLE, ASSOCIATION, MUTATION, PHOSPHORYLATION, IDENTIFICATION, PROTEOME |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10165080 |
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