Multi-omics analysis reveals CXCL14⁺ inhibitory neuron dysfunction in major depressive disorder

Major Depressive Disorder (MDD) is a complex psychiatric condition characterized by neuronal and functional disruptions in the dorsolateral prefrontal cortex (dlPFC). We integrated two single-nucleus RNA sequencing (snRNA-seq) datasets, GWAS summary data, and proteomic data from UK Biobank. We identified 273 MDD-associated expression quantitative trait loci (eQTL), while the single-cell disease-relevance score (scDRS) algorithm revealed that excitatory neurons, inhibitory neurons, and oligodendrocyte precursor cells (OPCs) are significantly associated with MDD. Non-negative matrix factorization (NMF) identified four meta-programs in neurons, reflecting functional impairments related to synaptic plasticity, neuronal connectivity, and epigenetic regulation. We characterized distinct pathological states of neuronal subtypes and identified CXCL14⁺ inhibitory neurons' role in stress perception. Plasma proteomic analyses provided independent peripheral support for five MDD associated risk genes whose encoded proteins showed prognostic value in CoxBoost models. Chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS) mouse models supported stress-induced alterations in prefrontal Cxcl14 expression. These findings provide a comprehensive understanding of MDD from a multi-omics perspective, offering potential diagnostic and therapeutic targets for MDD.