Reactive astrocyte-related pathogenic genes in depression: A multi-omics Mendelian randomization study

The pathogenic genes related to reactive astrocytes have been reported to be involved in depression, yet their associations remain unknown.

We curated 510 reactive astrocyte-related genes and integrated their methylation (mQTL), expression (eQTL) and protein (pQTL) quantitative trait loci data with large-scale depression GWAS (discovery: GWAS Catalog, replication: FinnGen). We employed the summary data-based Mendelian randomization (SMR) and colocalization analyses to identify potential associations. Additional tissue validation was performed using brain eQTL data, supplemented by expression detection and immunofluorescence for key genes in hippocampal tissues of chronic unpredictable mild stress (CUMS) mouse models.

The SMR analysis revealed 130 methylation sites (74 genes), 14 genes expression and 3 proteins associated with depression. In particular, the hypermethylation of LGALS3 was found to upregulate its expression and increase depression risk. The expression of PDGFA, as well as the expression and protein levels of GCDH, were also found to be positively associated with depression risk. Brain tissue-specific SMR further supported the disease-promoting role of GCDH and PDGFA. In vivo experiments in the CUMS mouse model demonstrated that hippocampal mRNA expression of LGALS3 was significantly upregulated, consistent with SMR predictions. In contrast, PDGFA mRNA was downregulated, suggesting a context-dependent role. Crucially, immunofluorescence staining of the hippocampus in the model group revealed an upregulation of the LGALS3 protein signal, occurring concurrently with a marked increase in the number of astrocytes in the same region.

Our study elucidated the potential involvement of reactive astrocyte-related genes, especially LGALS3, PDGFA, and GCDH.