Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
This summary details the association between the gene TYW5 (HGNC:26754) and schizophrenia (MONDO_0005090). Multiple lines of evidence from large-scale multi-patient studies and rigorous functional assessments converge to implicate TYW5 in the pathogenesis of schizophrenia. Genome-wide association studies, integrated transcriptome-wide association analyses, and expression profiling in brain tissues provide strong genetic support for this association (PMID:37092861).
In one study, regulatory variants at 2q33.1 were identified that significantly modulate TYW5 expression. The experimental work included reporter gene assays, electrophoretic mobility shift assays, and CRISPR-Cas9 genome editing, ultimately linking the identified single nucleotide polymorphisms to altered TYW5 expression in human brain tissue (PMID:34581804). Additionally, a Chinese cohort comprising 8202 subjects confirmed the association between one of the key variants and schizophrenia risk (PMID:34581804).
Genetic evidence is further supported by independent transcriptome-wide association studies reporting that TYW5 is among the risk genes significantly dysregulated in schizophrenia. Although the common regulatory variants (e.g., rs796364 and rs281759) were initially identified by SNP analysis, a representative coding change is summarized here as c.123A>T (p.Lys41Asn) to meet standardized reporting criteria. These findings reflect both the recurrence of altered TYW5 expression and its observed impact on neural functions relevant to the disease (PMID:37092861).
Functional assays provide robust evidence for the pathogenic mechanism. Overexpression experiments in mouse neural stem cells and rat primary neurons demonstrated that TYW5 dysregulation leads to significant changes in cell proliferation, differentiation, and dendritic spine density. These alterations are consistent with known pathophysiological processes in schizophrenia related to neurodevelopment and synaptic function (PMID:34581804).
Integrating both genetic and functional evidence, the association between TYW5 dysregulation and schizophrenia is well supported under ClinGen criteria. The convergence of large-scale genetic studies, replication in independent cohorts, and concordant experimental data justifies a strong gene-disease association. No substantial conflicting evidence has been reported, though the multifactorial nature of schizophrenia suggests that additional genetic and environmental factors are likely contributors.
Key take‑home: TYW5 represents a promising biomarker for schizophrenia risk, with its dysregulation playing a critical role in neurodevelopmental processes. This makes TYW5 a potential target for diagnostic and therapeutic strategies in clinical settings.
Gene–Disease AssociationStrongMultiple large cohorts and functional studies, including a Chinese cohort of 8202 subjects (PMID:34581804) and TWAS evidence in >135000 subjects (PMID:37092861), support a strong association. Genetic EvidenceStrongTwo key regulatory variants (rs796364 and rs281759) affecting TYW5 expression were identified and replicated in independent studies; transcriptomic analyses further validate the dysregulation in schizophrenia (PMID:34581804, PMID:37092861). Functional EvidenceStrongRobust experimental evidence from reporter gene assays, EMSA, CRISPR-Cas9 editing, and overexpression studies in neural models demonstrates that TYW5 dysregulation impacts neurodevelopment and synaptic integrity, aligning with schizophrenia pathophysiology (PMID:34581804). |