Integrative Analysis of Major Depressive Disorder and Ovarian Cancer: From Genetic Association to Single-Cell Mechanisms

Background: Although emerging evidence indicates that major depressive disorder (MDD) raises the risk of developing ovarian cancer (OC) and worsens survival, the biological mechanisms underlying this relationship remain unclear. This study explores the MDD-OC association using single-cell transcriptomics and genetic approaches. Methods: Using single-cell RNA-seq profiles of peripheral blood from MDD and OC patients, we compared shifts in immune cell subsets and selected the consistently expanded CD8+ effector memory (CD8_EM) T cells population for follow-up, validated using flow cytometry. We integrated expression quantitative trait loci (eQTL) data from CD8_EM T cell-specific genes with OC genome-wide association study (GWAS) summary statistics through two-sample Mendelian randomization (MR). In vitro experiments were additionally conducted to assess CLSTN3’s role in OC cell proliferation. Results: Among the 554 differentially expressed genes (DEGs) identified in CD8_EM T cells, MR showed a nominal association between CLSTN3 and ovarian cancer risk (OR 1.21, 95% CI 1.03–1.43), though this did not withstand correction for multiple comparisons. Colocalization analysis confirmed that CLSTN3 expression, regulated by the genetic variant rs3759416, shares a causal variant with the OC GWAS signal (PPH4 = 99.99%). Functionally, siRNA-mediated CLSTN3 silencing in HOC7 cells significantly reduced cell viability (CCK-8 assay). Conclusions: By focusing on CD8_EM T cells shared by MDD and ovarian cancer, we identified CLSTN3 as a candidate molecule through nominated by the convergence of genetic, transcriptomic, and functional evidence. These findings provide preliminary insights into the connection between depression and OC, though further validation is warranted.