Multi-omics integration identifies NK cell dysregulation and a five-gene diagnostic signature in major depressive disorder.

Background: Major Depressive Disorder (MDD), a leading global disability affecting 280 million people, has poor treatment efficacy due to persistent biological variability involving cell-type-specific transcriptomic dysregulation and immune dysfunction, and integrated multi-omics approaches are vital to uncover pathways and therapeutic targets. Methods: This research utilized a comprehensive multi-omics approach, merging bulk RNA sequencing (RNA-seq) data from the GSE39653 dataset with single-cell RNA sequencing (scRNA-seq) data derived from peripheral blood mononuclear cells (PBMCs) of three MDD patients and three healthy controls. Analysis of differential gene expression (DEGs1) and identification of genes inside Weighted Gene Co-expression Network Analysis (WGCNA) modules were conducted using bulk RNA-seq data. Analysis of differential cell population abundance and differential gene expression (DEGs2) was performed on the scRNA-seq data. Detection of CD3 Results: In the RNA-seq analysis, 803 DEGs1 and 2080 WGCNA module genes were identified. scRNA-seq analysis revealed 1,539 DEGs2 and identified natural killer (NK) cells as a major dysfunctional immune cell subpopulation in MDD, exhibiting a significantly increased proportion (CD3 Conclusion: Our study establishes NK cell dysfunction as a core pathophysiological mechanism in MDD, characterized by cellular expansion and metabolic alterations. The identified key genes serve as robust diagnostic biomarkers and therapeutic targets. Elucidation of their regulatory networks provides critical insights for precision psychiatry interventions.