Human genetic risk for major depressive disorder implicates motor cortex PVALB⁺ inhibitory neurons

Major depressive disorder (MDD) is highly polygenic, but the cellular and anatomical contexts through which inherited risk contributes to disease biology remain incompletely understood. Here we integrated large-scale MDD genome-wide association studies with an adult human brain single-cell discovery atlas and five independent replication atlases spanning brain regions, developmental stages, species, and disease states, comprising more than five million cells and nuclei. Across complementary polygenic mapping frameworks, MDD genetic signals were preferentially enriched in neuronal populations and consistently prioritized the primary motor cortex (M1) as a key anatomical context of risk. Subtype-level analyses highlighted PVALB⁺ inhibitory neurons and Ex-L2/4 excitatory neurons, with integrative gene prioritization nominating CNNM2 as a leading PVALB⁺-linked MDD risk-gene candidate. CNNM2 ⁺ PVALB⁺ inhibitory neurons showed elevated genetic risk scores and were enriched for synaptic, membrane-potential, and activity-related programs. In chronic-stress mouse models, Cnnm2 protein levels were reduced in M1 PV⁺ and SST⁺ inhibitory neurons, and optogenetic activation of M1 PV⁺ neurons rescued stress-induced depression-like behaviours. Anatomical tracing and activity mapping further implicated an M1–l/vlPAG circuit axis in exercise-associated antidepressant-like effects. These findings connect MDD polygenic risk to motor-cortical inhibitory-neuron biology and experimentally tractable circuit mechanisms and provide scDepBrain as a resource for exploring MDD-associated cellular programs across the brain.