Neuronal Cell-Specific sc-eQTL and Integrative eQTL-pQTL Mendelian Randomization Prioritize CKAP2 as a Candidate Gene for Major Depressive Disorder.

Major depressive disorder (MDD) constitutes a substantial global health burden; however, the causal genes and cell-type-specific mechanisms underlying its pathogenesis remain incompletely understood. We conducted an integrative transcriptomic and proteomic Mendelian randomization (MR) study incorporating expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets to prioritize genes associated with MDD. Candidate genes were further evaluated using neuron-specific single-cell eQTL analyses across multiple brain cell types, and brain imaging-derived phenotypes were assessed as exploratory structural mediators through two-step MR mediation analysis. Integrative eQTL-MR and pQTL-MR analyses identified 20 genes associated with MDD at both transcriptomic and proteomic levels. Notably, CKAP2 showed directionally discordant associations across molecular layers: genetically predicted CNS-related CKAP2 expression was inversely associated with MDD risk, whereas genetically predicted plasma CKAP2 protein levels showed an association in the opposite direction. Rather than establishing a unified causal mechanism across transcriptomic and proteomic layers, this discordance suggests that CKAP2-related genetic signals may differ across tissues, molecular layers, or instrument constructions. Single-cell eQTL analyses provided supportive evidence for a protective-direction association of CKAP2 expression in excitatory neurons (OR = 0.986, p = 0.007), inhibitory neurons (OR = 0.990, p = 0.007), and oligodendrocyte precursor cells (OR = 0.987, p = 0.009). Mediation analysis suggested that right thalamic ventral anterior nucleus volume may represent an exploratory imaging phenotype related to the CKAP2-MDD association, accounting for 17.0% of the total effect, although this finding requires independent replication. Sensitivity analyses provided no evidence of heterogeneity or horizontal pleiotropy, and reverse MR analyses showed no evidence of reverse causation, although these analyses were limited in statistical power. Collectively, these findings prioritize CKAP2 as a candidate gene with convergent but non-confirmatory genetic evidence for involvement in MDD, warranting further validation in independent causal and experimental frameworks.