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

Background Schizophrenia is a severe neuropsychiatric disorder characterized by altered perception, mood, and behavior that profoundly impacts patients and society despite its relatively low prevalence. Previous studies have suggested that the dopamine D2 receptor gene and genes involved in glutamatergic neurotransmission, synaptic plasticity, and immune function as genetic risk factors. Sex-based differences also exist in schizophrenia epidemiology, symptomatology and outcomes; however, we lack a transcriptomic profile that considers sex and differentiates specific cerebral regions. Methods 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. Results We discovered the sex-based dysregulation of 265 genes in the prefrontal, 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 female 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. Conclusions 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. Plain language summary Schizophrenia is a severe neuropsychiatric disorder characterized by altered perception, mood, and behavior that profoundly impacts patients and society. Previous studies have suggested dopamine and glutamate neurotransmission genes, as well as immune function alteration as genetic risk factors. Schizophrenia epidemiology, symptomatology and outcomes are different for women and men, but the biological reason is not understood. Therefore, we reviewed all RNA-sequencing studies of post-mortem brain samples of women and men affected by schizophrenia available. Then, we compared the gene expression on each study for males and females and integrated the results of studies on different regions meta-analyses: prefrontal cortex, hippocampus and all-studies. Finally, we 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 genes unveiled increased immune response functions in the prefrontal cortex in men and the hippocampus in women schizophrenia patients, as well as increased neurotransmission and synapses in the prefrontal cortex of female schizophrenia patients. The protein-protein interaction networks and transcription factors activity analyses supported these sex-based profiles. Our results report multiple 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. Highlights The expression of 265 genes is altered in the prefrontal cortex of schizophrenic patients, being overexpressed in females those related to synaptic transmission. In the prefrontal cortex of males, overexpressed genes and overactivated transcription factors are linked to immune response and inflammation. Conversely, genes and transcription factors more activated in the hippocampus of females are related to immune response, whereas those genes more expressed in males are linked to protein processing. The global meta-analysis unveils groups of long non-coding genes and pseudogenes differentially expressed in males and females. The effects of schizophrenia are closely related in the prefrontal cortex of males and the hippocampus of females.