The impact of sex on gene expression in the brain of schizophrenic patients: a systematic review and meta-analysis of transcriptomic studies

Schizophrenia is a severe neuropsychiatric disorder characterized by altered perception, mood, and behavior that profoundly impacts patients and society despite its relatively low prevalence. Sex-based differences have been described in schizophrenia epidemiology, symptomatology and outcomes. Different studies explored the impact of schizophrenia in the brain transcriptome, however we lack a consensus transcriptomic profile that considers sex and differentiates specific cerebral regions. We performed a systematic review on bulk RNA-sequencing studies of post-mortem brain samples. Then, we fulfilled differential expression analysis on each study and summarized their results with regions-specific meta-analyses (prefrontal cortex and hippocampus) and a global all-studies meta-analysis. Finally, we used the consensus transcriptomic profiles to functionally characterize the impact of schizophrenia in males and females by protein-protein interaction networks, enriched biological processes and dysregulated transcription factors. We discovered the sex-based dysregulation of 265 genes in the prefrontal cortex, 1.414 genes in the hippocampus and 66 genes in the all-studies meta-analyses. The functional characterization of these gene sets unveiled increased processes related to immune response functions in the prefrontal cortex in male and the hippocampus in female schizophrenia patients and the overexpression of genes related to neurotransmission and synapses in the prefrontal cortex of female schizophrenia patients. Considering a meta-analysis of all brain regions available, we encountered the relative overexpression of genes related to synaptic plasticity and transmission in females and the overexpression of genes involved in organizing genetic information and protein folding in male schizophrenia patients. The protein-protein interaction networks and transcription factors activity analyses supported these sex-based profiles. Our results report multiple sex-based transcriptomic alterations in specific brain regions of schizophrenia patients, which provides new insight into the role of sex in schizophrenia. Moreover, we unveil a partial overlapping of inflammatory processes in the prefrontal cortex of males and the hippocampus of females.