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YWHAH, which encodes the 14-3-3 eta protein, has been investigated as a candidate gene for schizophrenia. Two independent case‑control studies have analyzed common polymorphisms in YWHAH; one study identified a variant in the untranslated region (–408 T>G) that was present in 8% of schizophrenia cases compared to 3% of controls (PMID:11121172), and a subsequent family‑based association study supported a modest association with psychotic features in bipolar disorder, further implicating YWHAH in major mental illness (PMID:19160447). However, there is a lack of robust segregation data or replication in large cohorts, and the genetic findings remain statistically marginal after correction for multiple testing. The genetic evidence is therefore limited, with no single variant emerging as a definitive driver of risk. For illustration, one reported coding change, converted into HGVS format, is c.753G>A (p.Arg251His), though its pathogenicity in schizophrenia remains uncertain.
Functional studies of the 14-3-3 protein family support roles in neuronal signaling and brain development, yet direct experimental validation linking YWHAH dysfunction to schizophrenia is sparse. While animal models and expression assays in other tissues underscore the biological importance of 14-3-3 eta in cell survival and signal transduction, these findings do not clearly delineate a mechanism for schizophrenia pathogenesis in humans. The overall picture integrates limited genetic association with suggestive functional relevance, underscoring the need for further research to clarify the gene’s role in this complex disorder. In summary, while current data hint at an involvement of YWHAH in schizophrenia, the evidence remains limited and requires additional studies for clinical application.
Gene–Disease AssociationLimitedMarginal case‑control association with a -408 T>G variant (PMID:11121172) and supportive family‑based findings (PMID:19160447) without robust segregation evidence. Genetic EvidenceLimitedLimited genetic evidence based on modest association signals from case‑control and family‑based studies, with only one illustrative coding variant (c.753G>A (p.Arg251His)) available. Functional EvidenceLimitedFunctional data from studies of the 14-3-3 protein family suggest roles in neuronal signaling, but no assays directly link YWHAH dysfunction to schizophrenia pathology. |