Elevated endothelial cell signatures in major depressive disorder: A two-cohort transcriptomic concordance study

Major Depressive Disorder (MDD) lacks objective molecular biomarkers and is diagnosed clinically. Bulk blood transcriptomics shows immune-inflammatory dysregulation in MDD but obscures the cell populations driving disease, and recent work highlighting an elevated endothelial signature has lacked independent validation. We conducted a two-stage study using public datasets, performing cell-type deconvolution with marker panels for seven cell types in a discovery cohort (GSE54564, n = 42) to nominate candidates, then tested these for concordance in a larger independent cohort (GSE98793, n = 192) serving as the primary basis for inference. Genes correlated with endothelial scores in both cohorts were identified; pathway enrichment was performed with Enrichr; weighted gene co-expression network analysis (WGCNA) examined network-level associations; and multivariate regression assessed robustness to age, anxiety, sex, and microarray batch. Endothelial cells showed elevated scores in MDD in discovery (Cohen's d = 0.78, p = 0.053) and were similarly elevated in the validation cohort (d = 0.52, p = 0.001, FDR = 0.008); no other cell type met replication criteria. 271 consensus genes correlated with endothelial scores (160 positive, 111 negative), with enrichment for tight junction assembly, blood-brain barrier maintenance, and type I interferon signaling. WGCNA identified a 3409-gene module strongly correlated with endothelial scores (r = 0.52, p < 0.001), and the association persisted after adjustment (β = 0.267, p = 0.002), with comparable effects in patients with and without comorbid anxiety. These findings support a vascular-inflammatory hypothesis of depression and suggest that elevated endothelial signatures may characterise a biologically distinct patient subgroup, with endothelial markers representing candidate blood-based biomarkers warranting prospective validation.