Shared Immunogenetic Basis Between Spleen Volume and Psychiatric Disorders

Psychiatric disorders are closely linked to immune dysregulation, yet the genetic relationships between peripheral immune organs, particularly the spleen, and different psychiatric disorders remain poorly understood. This study aimed to explore these associations. Linkage disequilibrium score regression (LDSC) was used to evaluate the genetic correlations between spleen volume and schizophrenia, bipolar disorder, and depression. For the two traits showing significant genetic correlation, MAGMA gene-level analysis was further performed to identify significant overlapping genes as shared genes. KEGG and GO enrichment analyses were then conducted for these shared genes. In addition, a protein-protein interaction (PPI) network was constructed based on the STRING database, and hub genes were identified using the CytoHubba plugin in Cytoscape. Meanwhile, cell-type enrichment analysis was performed using single-cell transcriptomic reference datasets from the human cortex, hippocampus, and midbrain to localize the potential cellular context underlying the relevant genetic signals. To further investigate the potential functional genomic effects of spleen volume-associated genetic signals in depression-relevant brain regions, transcriptome-wide association study (TWAS) analyses were performed for spleen volume in the human prefrontal cortex and hippocampus. Functional enrichment analyses were subsequently conducted for the overlapping TWAS-associated genes identified in these two regions. Among the three major psychiatric disorders, only depression showed a significant genetic correlation with spleen volume. Spleen volume and depression shared 25 genes, which were mainly enriched in immune- and inflammation-related pathways, including antigen processing and presentation, natural killer cell-mediated cytotoxicity, NF-κB signaling, MAPK signaling, phagosome, and lysosome biogenesis. PPI network analysis further identified several hub genes closely related to immune regulation. Single-cell analysis revealed that the relevant genetic signals were significantly enriched in microglia across the cortex, hippocampus, and midbrain. Additional TWAS analyses in the prefrontal cortex and hippocampus identified 19 overlapping spleen volume-associated transcriptomic genes, with enrichment in immune-inflammatory regulation, monoamine neurotransmitter metabolism, apoptosis, and tryptophan metabolism-related pathways. Spleen volume and depression may share an immunoinflammatory genetic basis and may be linked through microglia-mediated central immune mechanisms, providing new genetic evidence for understanding spleen-brain axis interactions in depression.