Multi-omics integration identifies COQ8A in excitatory neurons as a protective gene in major depressive disorder

The pathogenesis of major depressive disorder (MDD) remains insufficiently understood, which may be due to the limitations of bulk tissue analyses in addressing cellular heterogeneity. In this study, we applied a comprehensive approach combining brain cell-type-specific expression quantitative trait loci data, MDD genome-wide association study summary statistics, and MDD single-nucleus RNA sequencing (snRNA-seq) data, with the aim of identifying cell-specific key genes. The utilization of summary-based mendelian randomization and two-sample mendelian randomization analyses resulted in the discovery of 26 candidate genes, of which 15 exhibited strong colocalization signals across four distinct brain cell types. Combining snRNA-seq data analysis, we discovered that COQ8A is down-regulated in excitatory neurons (Ex) and LATS1 is up-regulated in oligodendrocytes in MDD patients. These findings were further validated by mice chronic social defeat stress models, which demonstrated significant downregulation of COQ8A in Ex of prefrontal cortex (PFC). Functional analysis suggests a relationship between the down-regulated expression of COQ8A in Ex from the MDD group and impaired energy metabolism, mitochondrial function, and protein synthesis. Molecular docking and molecular dynamics simulations indicated that eight antidepressants bind to COQ8A with high affinity, with Escitalopram and Paroxetine effectively stabilizing its active sites. Our findings indicate that COQ8A in Ex of the PFC, associated with mitochondrial function, may serve as a key protective gene in MDD. Furthermore, COQ8A emerges as a promising therapeutic target for precision antidepressant treatment. This study enhances our understanding of the neurobiological basis of MDD at the single-cell level.