Summary: New research shows that the neurobiology of schizophrenia differs substantially between males and females. Using neurons made from induced pluripotent stem cells (iPSCs), researchers identified sex-specific transcriptional and proteomic signatures linked to schizophrenia, highlighting altered pathways in glycosaminoglycan metabolism, neurotransmitter processing and GABAergic synapses. A notably large share of schizophrenia-associated genes display sex-specific expression, suggesting the disorder’s mechanisms and potentially optimal treatments may differ by sex.
Source: University of Eastern Finland
Overview
Researchers from the University of Eastern Finland, the University of Helsinki and Karolinska Institutet report that the biological underpinnings of schizophrenia show pronounced sex differences. Published in Nature Communications, the study used neurons derived from induced pluripotent stem cells to compare gene and protein expression patterns in monozygotic twins discordant for schizophrenia and in healthy control samples. The findings point to sex-specific molecular signatures that could inform more tailored approaches to diagnosis and therapy.
Study design and methods
To minimize genetic variability, the team analyzed neurons produced from iPSCs reprogrammed from participants’ skin cells, focusing especially on identical twin pairs where only one twin has schizophrenia. This design strengthens the ability to detect disease-related molecular changes while controlling for inherited genetic background. The iPSC-derived neurons correspond developmentally to the second trimester of pregnancy, allowing the investigators to probe early neurodevelopmental differences associated with schizophrenia.
Comprehensive transcriptomic and proteomic analyses were performed to identify altered genes, proteins and biological pathways. By contrasting affected and unaffected twins and comparing male and female samples, the researchers isolated illness-specific signals and determined which changes were sex dependent.
Key findings
- Schizophrenia is associated with dysregulation in several biological pathways, notably glycosaminoglycan metabolism, neurotransmitter metabolism and GABAergic synapse function. Proteomic and pathway analyses also implicated sialylation and purine metabolism.
- Although only about 12% of all 19,462 genes examined differed in expression between healthy males and females, up to 61% of the genes linked to the illness showed sex-specific expression patterns. These sex-specific gene signatures were validated in an independent dataset, strengthening the evidence that the disease biology diverges between males and females.
- Because the iPSC-derived neurons model a mid-gestation stage of development, the results suggest that schizophrenia-related molecular changes can be present very early in brain development, and that differences between genetically identical individuals may emerge in utero.
Interpretation and clinical implications
The discovery that many illness-related genes are sex-specific offers a plausible explanation for why schizophrenia typically emerges after adolescence: gene expression of numerous sex-dependent genes changes around puberty, which could unmask or amplify vulnerability. The results imply that the pathophysiology of schizophrenia is at least partly distinct in males and females, and they underscore the potential value of developing sex-informed diagnostic criteria and therapeutic strategies. In short, precision approaches that account for sex differences could improve outcomes.
Source:
University of Eastern Finland
Media Contacts:
Jari Koistinaho – University of Eastern Finland
Image Source:
The image is in the public domain.
Original Research: Open access
“Sex-specific transcriptional and proteomic signatures in schizophrenia”. Authors: Jari Tiihonen, Marja Koskuvi, Markus Storvik, Ida Hyötyläinen, Yanyan Gao, Katja A. Puttonen, Raisa Giniatullina, Ekaterina Poguzhelskaya, Ilkka Ojansuu, Olli Vaurio, Tyrone D. Cannon, Jouko Lönnqvist, Sebastian Therman, Jaana Suvisaari, Jaakko Kaprio, Lesley Cheng, Andrew F. Hill, Markku Lähteenvuo, Jussi Tohka, Rashid Giniatullin, Šárka Lehtonen, Jari Koistinaho and colleagues. Published in Nature Communications.
Abstract (summary)
The study addresses why schizophrenia typically appears after adolescence and what neurobiological mechanisms lead to the onset of illness. Using iPSC-derived neurons from monozygotic twins discordant for schizophrenia, the authors reduced genetic heterogeneity to enhance detection of disease-specific signals. Proteomic and pathway analyses associated clinical illness with altered glycosaminoglycan metabolism, GABAergic synapse function, sialylation and purine metabolism. While only 12% of the ~19,462 genes examined were differentially expressed between healthy males and females, up to 61% of illness-related genes were sex specific. Replication in an independent dataset supports the conclusion that schizophrenia’s pathophysiology differs between sexes, which may help explain the adolescent onset and argues for consideration of sex-specific treatments.