The Impact of Sex on Gene Expression in the Brain of Schizophrenic Patients: a Systematic Review and Meta-analysis of Transcriptomic Studies

Overview

Journal Biol Sex Differ

Publisher Biomed Central

Specialties Biology
Physiology

Date 2024 Jul 27

PMID 39068467

Authors

Hector Carceller

Marta R Hidalgo

Maria Jose Escarti

Juan Nacher

Maria de la Iglesia-Vaya

Francisco Garcia-Garcia

Affiliations

Soon will be listed here.

Abstract

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. 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.

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 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.

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.

Citing Articles

Single-Cell Transcriptional Profiling Reveals Cell Type-Specific Sex-Dependent Molecular Patterns of Schizophrenia.

Zhou R, Zhang T, Sun B Int J Mol Sci. 2025; 26(5).

PMID: 40076849 PMC: 11900070. DOI: 10.3390/ijms26052227.

References

Schmidt M, Mirnics K . Neurodevelopment, GABA system dysfunction, and schizophrenia. Neuropsychopharmacology. 2014; 40(1):190-206. PMC: 4262918. DOI: 10.1038/npp.2014.95. View

Schubert K, Focking M, Cotter D . Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: potential roles in GABAergic interneuron pathology. Schizophr Res. 2015; 167(1-3):64-72. DOI: 10.1016/j.schres.2015.02.002. View

Nishimura A, Ikemoto K, Satoh K, Yamamoto Y, Rand S, Brinkmann B . The carbohydrate deposits detected by histochemical methods in the molecular layer of the dentate gyrus in the hippocampal formation of patients with schizophrenia, Down's syndrome and dementia, and aged person. Glycoconj J. 2001; 17(11):815-22. DOI: 10.1023/a:1010996911581. View

Murphy C, Walker A, Weickert C . Neuroinflammation in schizophrenia: the role of nuclear factor kappa B. Transl Psychiatry. 2021; 11(1):528. PMC: 8516884. DOI: 10.1038/s41398-021-01607-0. View

Volk D, Chitrapu A, Edelson J, Roman K, Moroco A, Lewis D . Molecular mechanisms and timing of cortical immune activation in schizophrenia. Am J Psychiatry. 2015; 172(11):1112-21. PMC: 5063256. DOI: 10.1176/appi.ajp.2015.15010019. View

. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014; 511(7510):421-7. PMC: 4112379. DOI: 10.1038/nature13595. View

Chang X, Liu Y, Hahn C, Gur R, Sleiman P, Hakonarson H . RNA-seq analysis of amygdala tissue reveals characteristic expression profiles in schizophrenia. Transl Psychiatry. 2017; 7(8):e1203. PMC: 5611723. DOI: 10.1038/tp.2017.154. View

Catala-Senent J, Andreu Z, Hidalgo M, Soler-Saez I, Roig F, Yanguas-Casas N . A deep transcriptome meta-analysis reveals sex differences in multiple sclerosis. Neurobiol Dis. 2023; 181:106113. DOI: 10.1016/j.nbd.2023.106113. View

Ochoa D, Hercules A, Carmona M, Suveges D, Gonzalez-Uriarte A, Malangone C . Open Targets Platform: supporting systematic drug-target identification and prioritisation. Nucleic Acids Res. 2020; 49(D1):D1302-D1310. PMC: 7779013. DOI: 10.1093/nar/gkaa1027. View

10.

Aleman A, Kahn R, Selten J . Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch Gen Psychiatry. 2003; 60(6):565-71. DOI: 10.1001/archpsyc.60.6.565. View

11.

Martins-de-Souza D, Maccarrone G, Wobrock T, Zerr I, Gormanns P, Reckow S . Proteome analysis of the thalamus and cerebrospinal fluid reveals glycolysis dysfunction and potential biomarkers candidates for schizophrenia. J Psychiatr Res. 2010; 44(16):1176-89. DOI: 10.1016/j.jpsychires.2010.04.014. View

12.

Rajarethinam R, DeQuardo J, Miedler J, Arndt S, Kirbat R, Brunberg J . Hippocampus and amygdala in schizophrenia: assessment of the relationship of neuroanatomy to psychopathology. Psychiatry Res. 2001; 108(2):79-87. DOI: 10.1016/s0925-4927(01)00120-2. View

13.

Kaalund S, Newburn E, Ye T, Tao R, Li C, Deep-Soboslay A . Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain. Mol Psychiatry. 2013; 19(12):1258-66. DOI: 10.1038/mp.2013.165. View

14.

Hu J, Xu J, Pang L, Zhao H, Li F, Deng Y . Systematically characterizing dysfunctional long intergenic non-coding RNAs in multiple brain regions of major psychosis. Oncotarget. 2016; 7(44):71087-71098. PMC: 5342065. DOI: 10.18632/oncotarget.12122. View

15.

Bergman O, Karry R, Milhem J, Ben-Shachar D . NDUFV2 pseudogene (NDUFV2P1) contributes to mitochondrial complex I deficits in schizophrenia. Mol Psychiatry. 2018; 25(4):805-820. DOI: 10.1038/s41380-018-0309-9. View

16.

Lanz T, Reinhart V, Sheehan M, Sukoff Rizzo S, Bove S, James L . Postmortem transcriptional profiling reveals widespread increase in inflammation in schizophrenia: a comparison of prefrontal cortex, striatum, and hippocampus among matched tetrads of controls with subjects diagnosed with schizophrenia, bipolar or.... Transl Psychiatry. 2019; 9(1):151. PMC: 6533277. DOI: 10.1038/s41398-019-0492-8. View

17.

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

18.

DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials. 1986; 7(3):177-88. DOI: 10.1016/0197-2456(86)90046-2. View

19.

Zhang Y, Catts V, Sheedy D, McCrossin T, Kril J, Weickert C . Cortical grey matter volume reduction in people with schizophrenia is associated with neuro-inflammation. Transl Psychiatry. 2016; 6(12):e982. PMC: 5290336. DOI: 10.1038/tp.2016.238. View

20.

Nucifora L, MacDonald M, Lee B, Peters M, Norris A, Orsburn B . Increased Protein Insolubility in Brains From a Subset of Patients With Schizophrenia. Am J Psychiatry. 2019; 176(9):730-743. DOI: 10.1176/appi.ajp.2019.18070864. View