Li Yang, Miao Yahu, Feng Qing, Zhu Weixi, Chen Yijing, Kang Qingqing, Wang Zhen, Lu Fangting, Zhang Qiu
Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, China.
Front Endocrinol (Lausanne). 2024 Aug 30;15:1401531. doi: 10.3389/fendo.2024.1401531. eCollection 2024.
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.
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.
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 (), 3-hydroxyisobutyryl-CoA hydrolase (), and iron-sulfur cluster assembly 2 () were identified as Tier 1 genes, showing causal links with T2DM and strong colocalization evidence. and were causally associated with an increased risk of T2DM, while showed an inverse causal relationship. The causal associations and colocalization effects for and were validated in specific tissues. was also found to be a risk factor for microvascular complications in T2DM patients including retinopathy, nephropathy, and neuropathy. Furthermore, drug target analysis and phenome-wide MR underscored their significance as potential therapeutic targets.
This study identified 18 mitochondrial-related genes causally associated with T2DM at multi-omics levels, enhancing the understanding of mitochondrial dysfunction in T2DM and its complications. , , and emerge as potential therapeutic targets for T2DM and its complications.
线粒体功能障碍在2型糖尿病（T2DM）及其并发症中起关键作用。然而，其遗传病理生理学仍在研究中。通过多组学孟德尔随机化（MR）和共定位分析，我们确定了与T2DM及其并发症存在因果关系的线粒体相关基因。
从欧洲队列研究中检索甲基化、RNA和蛋白质水平的汇总水平定量性状位点数据。T2DM及其并发症的全基因组关联研究（GWAS）汇总统计数据分别从DIAGRAM和芬兰基因组联盟收集。基于汇总数据的MR用于估计因果效应。依赖工具测试中的异质性评估水平多效性，而共定位分析确定基因和疾病是否共享相同的因果变异。进行富集分析、药物靶点分析和全表型组MR以进一步探索生物学功能、潜在药物以及与其他疾病的因果关联。
整合多组学证据，我们确定了18个因果线粒体相关基因。富集分析表明它们不仅与营养物质代谢有关，还与线粒体自噬、自噬和凋亡等过程有关。在这些基因中，线粒体Tu翻译延伸因子（）、3-羟基异丁酰辅酶A水解酶（）和铁硫簇组装2（）被确定为一级基因，显示出与T2DM的因果关系和强共定位证据。和与T2DM风险增加存在因果关联，而显示出反向因果关系。和的因果关联和共定位效应在特定组织中得到验证。还被发现是T2DM患者微血管并发症（包括视网膜病变、肾病和神经病变）的危险因素。此外，药物靶点分析和全表型组MR强调了它们作为潜在治疗靶点的重要性。
本研究在多组学水平上确定了18个与T2DM存在因果关系的线粒体相关基因，加深了对T2DM及其并发症中线粒体功能障碍的理解。、和成为T2DM及其并发症的潜在治疗靶点。
