Systems-level transcriptomic analysis reveals synapse-related gene dysregulation in peripheral leukocytes of MDD patients, 2026, Adri et al.

[SNT Gatchaman]

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

Spoiler: Authors

Adri, Anny Silva; Nóbile, Adriel Leal; de Albuquerque, Débora Gomes; Barcelos, Pedro Marçal; do Vale, Fernando Yuri Nery; Nava, Roseane Galdioli; Correa, Yohan Lucas G; Schimke, Lena Friederick; Onuchic, Luiz Fernando; Dalmolin, Rodrigo; Rezende, Rafael Machado; Dias, Haroldo Dutra; Filgueiras, Igor Salerno; Cabral-Marques, Otavio

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.

Web | DOI | PDF | Nature Scientific Reports | Open Access

 

[SNT Gatchaman]

Our annotation identified 73 synapse-related metaDEGs in peripheral leukocytes (48 downregulated and 25 upregulated; Fig. 2a). Among these, we prioritized the top 15 genes enriched in synaptic BPs (padj < 0.05): NLGN1, CDK5, OTOF, GIT1, STX1A, PLD2, BCR, IQSEC2, CACNA1B, MAPK8IP2, DOC2A, STX2, KIF1A, LZTS3, and MX1. These DEGs are involved in key functions such as synaptic vesicle cycling, modulation of chemical synaptic transmission, synaptic exocytosis, and dendritic spine morphogenesis. The network analysis (Fig. 2b; Supplementary Table 3) places these genes within their associated BPs, underscoring their dual annotation in immune- and nervous system–related pathways.

This work provides a systems-level overview of transcriptional alterations in peripheral leukocytes from MDD patients, focusing on genes annotated to synaptic processes. Rather than implying equivalence between blood and brain expression, our approach identifies in peripheral leukocytes a reproducible subset of synaptic-related genes that discriminate MDD patients from controls across independent datasets. These findings offer a new perspective on how traditionally neuronal-associated genes may participate in immune-related processes that warrant further investigation.

In our meta-analysis, we identified 73 synaptic-related metaDEGs in peripheral leukocytes, including genes involved in the synaptic vesicle cycle 50 and synaptic assembly. These findings suggest that the enrichment results can indicate that immune cells can express genes involved in nervous system processes, potentially with distinct immune-specific roles previously unidentified.

Notably, genes such as MDGA135 , PICK169 , BCR28 , 37 , MX134 , MYLK 36 and GNB3 are involved in synaptic processes, including the regulation of presynapse assembly and trans-synaptic signaling, and glutamate neurotransmission, where molecular pathways are essential for maintaining synaptic organization and network integrity.

 

[V.R.T.]

These findings suggest that the enrichment results can indicate that immune cells can express genes involved in nervous system processes, potentially with distinct immune-specific roles previously unidentified.

This is really fascinating and very relevant to both theorising of immune brain signalling loops and to the oft repeated refrain around here that we're only or mostly seeing brain genes.

There is a lot of speculation in the direction of 'perhaps this immune clue is actually a brain clue'. But it would be very interesting if some of the brain clues were actually immune clues.

At the very least, this paper shows how deeply interlinked the immune system and CNS are.

I discovered the other day that BTN2A1 is highly expressed on CNS macrophages (and I think quite highly expressed on eMSNs although I was warned not to run away with that line of thought). This all seems very fertile ground for hypotheses.