Schizophrenia is a severe psychiatric disorder characterized by positive and negative symptoms, cognitive deficits, and substantial reductions in life expectancy. Circadian disturbances, including altered sleep patterns, locomotor activity, and clock gene expression, are increasingly recognized as important features of the disorder. Although genome-wide association studies (GWASs) have uncovered numerous schizophrenia susceptibility loci, how individual risk genes influence circadian regulation and synaptic function remains poorly understood.

In a recent study published in Genes & Diseases, researchers led by teams from the Kunming Institute of Zoology, Chinese Academy of Sciences, Southeast University, Kunming College of Life Science, Beijing Laboratory Animal Research Center, Xinxiang Medical University, Kunming Medical University, and Ningbo University identified TYW5 as a strongly supported schizophrenia risk gene within the 2q33.1 locus. By integrating genetic, epigenetic, brain expression, and transcriptomic evidence with mouse models, behavioral analyses, electron microscopy, and RNA sequencing, the investigators uncovered a potential connection between TYW5 dysregulation, circadian abnormalities, and altered synaptic organization.

A multidimensional prioritization framework identified three potentially functional variants—rs796364, rs281766, and rs2949006—and highlighted TYW5 among the leading candidate genes at 2q33.1. Brain expression analyses showed that schizophrenia-associated risk alleles were linked to reduced TYW5 expression, while transcriptomic datasets revealed increased TYW5 expression in the dorsolateral prefrontal cortex of patients with schizophrenia, underscoring the complex relationship between TYW5 dosage and disease biology.

To examine these effects experimentally, the researchers generated Tyw5 knockout (Tyw5-KO) mice using CRISPR/Cas9 and separately overexpressed human TYW5 (TYW5-OE) in the medial prefrontal cortex (mPFC) of wild-type mice using adeno-associated viruses. TYW5 deficiency produced gene dosage-dependent increases in locomotor activity, particularly during the nocturnal active phase. In contrast, TYW5 overexpression in the mPFC induced anxiety-like behavior and reduced locomotor activity during specific nighttime periods, suggesting that both reduced and elevated TYW5 expression can perturb circadian activity in distinct directions.

Electron microscopy provided further mechanistic insight, showing that TYW5 overexpression selectively increased synaptic vesicle density within presynaptic boutons without significantly altering overall synapse number, synaptic cleft dimensions, or postsynaptic density morphology. This synaptic remodeling may influence neurotransmitter release and contribute to the behavioral abnormalities associated with TYW5 dysregulation.

Transcriptomic profiling of the mPFC subsequently identified 30 differentially expressed genes, including the core circadian regulators Per1 and Per2, the immediate early gene Egr1, and tRNA metabolism-related genes Yars, Cars, and Mars1. Enrichment analyses implicated circadian rhythm, circadian entrainment, tRNA aminoacylation, GnRH signaling, and MAPK signaling, providing a molecular framework linking TYW5 activity with both biological timing and neuronal function.

Overall, the study positions TYW5 at the intersection of genetic susceptibility, synaptic regulation, and circadian biology in schizophrenia. By demonstrating that altered TYW5 dosage reshapes locomotor rhythms, presynaptic organization, and clock gene networks, these findings provide new mechanistic insight into schizophrenia-associated circadian abnormalities and establish TYW5-related pathways as promising directions for further investigation.

Reference

Title of Original Paper: Dysregulation of schizophrenia risk gene TYW5 in the mPFC alters circadian activity in male mice: Mechanistic insights into synaptic and transcriptional pathways
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2026.102284

Funding Information:

The Yunnan Revitalization Talent Support Program Top team (China) (No. 202505AT350003, No. 202405AS350022)
The National Natural Science Foundation of China (No. 82171511, No. U22A20304, No. 82571718)
The Yunnan Fundamental Research Projects (China) (No. 202301AW070009)
The Yunnan Revitalization Talent Support Program Young Talent Project

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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