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The association between the KMO gene (HGNC:6381) and schizophrenia (MONDO:0005090) has been investigated in case–control cohorts, with initial studies suggesting a potential link while subsequent analyses have yielded conflicting results. In a Japanese study, 465 cases and 440 controls were evaluated (PMID:16716206); a significant association of a KMO single nucleotide polymorphism was observed in this initial cohort. However, replication using an independent cohort of 480 cases and 448 controls did not confirm the association, indicating limited genetic support for a causative role.
Further genetic investigations have not identified additional segregating variants or familial transmission data to reinforce the association. The inconsistency in replication studies and the lack of a robust variant spectrum for KMO reduce the overall confidence in its direct genetic contribution to schizophrenia.
Functional assessments provide moderate support for the involvement of KMO. Evidence from functional studies demonstrates that risk alleles in KMO are associated with reduced gene expression in postmortem schizophrenia cortex and correlate with deficits in cognitive function (PMID:25464917). Additionally, an investigation into cerebrospinal fluid monoamine metabolite concentrations has implicated KMO variants as intermediate phenotypes in psychosis (PMID:26142836).
The integration of these findings indicates that while the genetic association remains limited and somewhat conflicted, the functional evidence supports a potential contributory role of altered KMO activity in the pathophysiology of schizophrenia. The absence of conclusive variant data and robust segregation information suggests that additional, larger studies are needed.
Moreover, the functional data — including altered enzyme expression and associated cognitive deficits — underscore that KMO may modify disease-related biological processes, even if its role as a primary causal gene is not definitively established. This discrepancy between genetic and functional observations highlights the complexity of the genetic architecture underlying schizophrenia.
In summary, although current genetic studies provide limited evidence due to inconsistent replication, the functional assays lend moderate support for KMO’s involvement in schizophrenia. This narrative informs diagnostic decision‑making and underscores the need for further research to validate the clinical utility of KMO as a marker in schizophrenia.
Key Take‑home sentence: Despite limited replication of genetic association, the supportive functional evidence for altered KMO expression and its impact on cognition offers a promising avenue for future exploration of schizophrenia mechanisms.
Gene–Disease AssociationLimitedA Japanese case–control study involving 465 cases (PMID:16716206) revealed a significant association that was not replicated in an independent cohort, limiting overall confidence in the association. Genetic EvidenceLimitedGenetic evidence is based on a single association study with conflicting replication results and lacks comprehensive segregation and variant data (PMID:16716206). Functional EvidenceModerateFunctional assessments demonstrate that KMO variations correlate with reduced cortical expression and cognitive deficits in schizophrenia (PMID:25464917), supporting a contributory role. |