Biological mechanism and functional verification of key genes related to major depressive disorder and type 2 diabetes mellitus

• Published in: Mammalian genome Vol. 36; no. 1; pp. 66 - 82
• Main Authors: Fang, Tao, Shen, Na, Shi, Zhemin, Luo, Weishun, Di, Yanbo, Liu, Xuan, Ma, Shengnan, Wang, Jing, Hou, Shike
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.03.2025; Springer Nature B.V
• Subjects: Amino acids; Animal Genetics and Genomics; Apoptosis; Biomedical and Life Sciences; biosynthesis; Cell Biology; Cell death; Cell signaling; data collection; Databases, Genetic; Depressive Disorder, Major - genetics; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; DNA microarrays; Enzymatic activity; enzyme activity; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Gene set enrichment analysis; gene targeting; Genes; Human Genetics; Humans; Life Sciences; Mental depression; microarray technology; mitochondria; Molecular modelling; noninsulin-dependent diabetes mellitus; Therapeutic targets; therapeutics; Type 2 diabetes; Bioinformatics analysis; Hub gene; Major depressive disorder; Verification of functionality
• ISSN: 0938-8990; 1432-1777; 1432-1777
• DOI: 10.1007/s00335-024-10090-z

Major depressive disorder (MDD) and type 2 diabetes (T 2 D) have been shown to be linked, but a comprehensive understanding of the underlying molecular mechanisms remains elusive. The purpose of this study was to explore the biological relationship between MDD and T 2 D and verify the functional roles of key genes. We used the Gene Expression Omnibus database to investigate the targets associated with MDD and T 2 D. Using linear models for microarray data, differentially expressed genes associated with MDD and T 2 D were identified in GSE76826 and GSE95849, respectively, and 126 shared genes were significantly upregulated. Weighted gene coexpression network analysis identified modules associated with MDD and T 2 D in the GSE38206 and GSE20966 datasets and identified 8 common genes. Functional enrichment analysis revealed that these genes were enriched in cell signaling, enzyme activity, cell structure and amino acid biosynthesis and involved in cell death pathways. Finally, combined with the CTD and GeneCards databases, lysophosphatidylglycerol acyltransferase 1 (LPGAT1) was identified as a key gene. LPGAT1 was validated in GSE201332 and GSE182117, and the subject operating characteristic curve showed good diagnostic potential for MDD and T 2 D. Additionally, we used an in vitro model of MDD related to T 2 D to verify the expression of LPGAT1. A subsequent gene knockdown assay revealed that the downregulation of LPGAT1 improved mitochondrial function and reduced apoptosis in damaged neurons. Taken together, our results highlight the role of LPGAT1 in the connection between MDD and T 2 D, and these findings provide new insights into potential therapeutic targets for depression associated with diabetes. Graphical abstract