Cell type-specific transcriptional features associated with gray matter volume alterations in schizophrenia with...

Negative symptoms are a major cause of disability in schizophrenia. The molecular and cellular mechanisms underlying this symptom domain remain unknown. We hypothesized that gray matter volume (GMV) alteration in schizophrenia patients with predominantly negative symptoms (PNS) may be associated with gene expression profiles of neurons and oligodendrocytes.

This cross-sectional study comprised 253 subjects, including 75 with PNS, 84 with predominantly positive symptoms (PPS) and 94 healthy controls. Group differences in GMV were analyzed, and partial least squares regression was employed to examine the association between GMV alterations in the PNS group and spatial gene expression patterns derived from the Allen Human Brain Atlas. A series of bioinformatics analyses-including functional enrichment, protein-protein interaction network analysis, and cell type-specific expression profiling-were conducted to identify potential molecular and cellular mechanisms underlying GMV alterations in the PNS group.

Relative to healthy controls, the PNS group displayed a greater number of regions with abnormal GMV than the PPS group, and exhibited smaller GMV in TE1.0/TE1.2_R but larger GMV in lsOccG_L in direct comparison with the PPS group. Genes associated with GMV alterations in the PNS group were enriched in biological processes at the synapse, protein catabolism and localization, etc., and shared enriched pathways with schizophrenia GWAS risk genes. The interregional profile of GMV differences in PNS was both negatively associated with expression profiles specific to excitatory and inhibitory neurons, and positively with those of oligodendrocytes.

This multimodal integration of neuroimaging and transcriptomic data suggests that GMV alterations in PNS may reflect disruptions in neurons and oligodendrocytes biological functions.