Novel insights into genetic associations and drug targets of mitochondria-associated proteins with major depressive disorder.

A growing number of observational studies have found that mitochondrial pathomechanisms are associated with major depressive disorder (MDD), but little is known about the causal direction of this association. This study aimed to explore the potential causal relationship between mitochondria-associated proteins and the risk of MDD. We used summary data from a genome-wide association study (GWAS) of 66 mitochondria-associated proteins in 3301 individuals of European descent, as well as a large GWAS on MDD, which involved 294,322 cases and 741,438 controls. We performed a two-sample bidirectional Mendelian randomization (MR) analysis using inverse variance weighting (IVW) as the primary method, supplemented by two additional approaches (MR-Egger and weighted median methods) as sensitivity analyses to detect and adjust for pleiotropy. Moreover, to identify and evaluate potential drug targets, we conducted searches in both the GWAS catalog and the Drug-Gene Interaction Database (DGIdb). According to MR analysis, gene-determined significant causal associations were found between TruA (OR: 0.98), HINT2 (OR: 0.98), MUL1 (OR: 0.98), C1QBP (OR: 1.02), and MDD. The reverse MR analysis indicated causal associations between MDD and RNMT (OR: 0.79), C1QBP (OR: 0.75), and ATPβ (OR: 0.77). Thus, we observed a clear bidirectional causal relationship between C1QBP and MDD. Following gene-drug analysis, CHF, BCHE, and KNG1 emerged as potential therapeutic targets. Our findings revealed a causal link between mitochondria-associated proteins and MDD, offering significantly new insights to augment the understanding of MDD pathomechanisms to identify potential therapeutic targets for drug development.