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The association between RTN4 (HGNC:14085) and schizophrenia (MONDO_0005090) remains highly controversial. One study, which evaluated a 3'UTR insertion polymorphism in 725 individuals, found no significant association with schizophrenia (PMID:15820318), while a subsequent Japanese case‑control study examining multiple single nucleotide polymorphisms reported nominal associations for two RTN4 variants (PMID:21563301). In the latter study, a missense change – reported as rs11677099 with a predicted amino‑acid substitution – was implicated, although in silico analysis suggested only a modest deleterious effect. Overall, these genetic findings have been inconsistent; the lack of robust statistical significance after multiple testing correction and the absence of supporting familial segregation data lessen the confidence in a direct genetic contribution of RTN4 to schizophrenia. The genetic evidence is further diluted by the failure to replicate findings across diverse populations and by the limited number of affected probands needed to reach any conclusive score.
In addition to the ambiguous genetic data, there is minimal functional evidence linking RTN4 to the pathogenesis of schizophrenia. While functional studies have examined RTN4 in the context of neural regeneration and other diseases, no direct experimental assay has confirmed a role for RTN4 variations in modulating neurobiological mechanisms underlying schizophrenia. The lack of corroborative functional assays or animal models that recapitulate a schizophrenia‐like phenotype further weakens the overall association. Given these factors, the current overall classification of the RTN4‑schizophrenia association is best characterized as disputed. Clinicians and researchers should interpret the available data with caution, recognizing that additional high‑quality studies are needed to clarify any potential role of RTN4 in schizophrenia risk.
Gene–Disease AssociationDisputedOne large study of 725 individuals (PMID:15820318) reported no association, while another Japanese case-control study (PMID:21563301) found nominal signals that did not remain significant after correction. Genetic EvidenceDisputedThe genetic evidence is limited to nominal associations without robust replication or familial segregation, thereby not meeting thresholds for stronger evidence. Functional EvidenceLimitedExisting functional studies on RTN4 focus on other disease contexts and do not provide direct mechanistic insights into schizophrenia pathogenesis. |