Identification of mitochondrial-related causal genes for major depression disorder via integrating multi-omics

Mitochondria dysfunction plays a pivotal role in major depressive disorder (MDD), but the causal link between mitochondria dysfunction and MDD remains unclear.

This study aimed to explore the causal effects of mitochondrial-related genes (MRGs) on MDD by integrating multi-omics data.

Summary statistics of DNA methylation, gene expression, and protein for MRGs were obtained from the corresponding quantitative trait loci in European ancestry individuals. GWAS summary statistics for MDD were sourced from the Psychiatric Genomics Consortium (PGC, discovery) and FinnGen R10 study (replication). Summary-data-based Mendelian Randomization (SMR) was performed to assess the association between DNA methylation, gene expression, and protein abundances of MRGs with the risk of MDD. Colocalization analysis was employed to assess the potential shared genetic variants between MRGs and MDD. Two-sample MR was conducted to assess the sensitivity of the SMR results. Single-nucleus RNA-sequencing (snRNA-seq) and bulk RNA-seq data were used to explore the candidate MRG expression.

We identified methylation levels of PPTC7 (cg08752433) and methylation levels of VRS2 (cg07945879, cg14935711, cg00244776, cg15848685, cg12457901, cg16958594) associated with a decreased risk of MDD. Conversely, the methylation levels of VRS2 (cg26784891, cg05853013, cg04966294) and MRPL46 (cg00200755) were associated with increased risk of MDD. High expression of COQ8A and TRMT10C were associated with an increased risk of MDD. Notably, COQ8A was predominantly expressed in both inhibitory and excitatory neurons in MDD patients.

This study established a causal relationship between mitochondrial dysfunction and MDD, identifying candidate MRGs, and providing potential diagnostic and therapeutic targets for MDD.