Mitochondrial dysfunction and onset of type 2 diabetes along with its complications: a multi-omics Mendelian randomization and colocalization study

作者：Yang Li, Yahu Miao, Qing Feng, Weixi Zhu, Yijing Chen, Qingqing Kang, Zhen Wang, Fangting Lu, Qiu Zhang · 发表于：Frontiers in Endocrinology · 年份：2024 · DOI：10.3389/fendo.2024.1401531 · 被引用次数：15 · 研究领域：Genetic Associations and Epidemiology、Mitochondrial Function and Pathology、Genetic Mapping and Diversity in Plants and Animals

Background Mitochondrial dysfunction plays a crucial role in Type 2 Diabetes Mellitus (T2DM) and its complications. However, the genetic pathophysiology remains under investigation. Through multi-omics Mendelian Randomization (MR) and colocalization analyses, we identified mitochondrial-related genes causally linked with T2DM and its complications. Methods Summary-level quantitative trait loci data at methylation, RNA, and protein levels were retrieved from European cohort studies. GWAS summary statistics for T2DM and its complications were collected from the DIAGRAM and FinnGen consortiums, respectively. Summary-data-based MR was utilized to estimate the causal effects. The heterogeneity in dependent instrument test assessed horizontal pleiotropy, while colocalization analysis determined whether genes and diseases share the same causal variant. Enrichment analysis, drug target analysis, and phenome-wide MR were conducted to further explore the biological functions, potential drugs, and causal associations with other diseases. Results Integrating evidence from multi-omics, we identified 18 causal mitochondrial-related genes. Enrichment analysis revealed they were not only related to nutrient metabolisms but also to the processes like mitophagy, autophagy, and apoptosis. Among these genes, Tu translation elongation factor mitochondrial ( TUFM ), 3-hydroxyisobutyryl-CoA hydrolase ( HIBCH ), and iron-sulfur cluster assembly 2 ( ISCA2 ) were identified as Tier 1 genes, showing ca...