Systems-level transcriptomic analysis reveals synapse-related gene dysregulation in peripheral leukocytes of MDD patients

Major depressive disorder (MDD) involves both central nervous system dysfunction and systemic immune alterations. Using a systems biology approach, we investigated whether peripheral leukocytes exhibit transcriptional changes in genes annotated to synaptic processes, molecular functions typically associated with neurons but also possibly implicated in immune cell biology. A meta-analysis of transcriptomic data from 3072 individuals identified 1383 meta-differentially expressed genes (metaDEGs) in leukocytes, including 73 whose known functions are linked to synaptic biology. Among them, functional enrichment analysis indicated synapse-related metaDEGs (48 downregulated, 25 upregulated) involved in synaptic vesicle cycling, neurotransmitter signaling, synaptic assembly, and neurogenesis. Linear discriminant analysis (LDA) identified 18 of these genes that robustly distinguished MDD patients from healthy controls across independent datasets. Notably, we identified metaDEGs shared between leukocytes and brain regions associated with MDD, indicating that genes traditionally linked to neuronal pathways are also expressed in immune cells, where they may contribute to immune-related mechanisms relevant to the disorder. These findings highlight potential systemic molecular patterns that warrant further investigation.