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TRIM26 (HGNC:12962) has emerged as one of several candidate genes implicated in schizophrenia (MONDO_0005090) through large‐scale multi‐patient studies. The investigation combined GWAS data, expression quantitative trait locus (eQTL) analyses, and neuroimaging approaches to uncover statistically significant association signals in genes located within the major histocompatibility complex (MHC) region (PMID:22433715, PMID:24160291). Although TRIM26 was not the sole gene implicated, its repeated emergence across independent assessments raises its profile as a potential contributor to the polygenic architecture of schizophrenia. In this context, the association is derived from population-level studies rather than family-based segregation analyses. The evidence is derived from well-powered cohorts and analytic strategies that integrate genetic and transcriptomic data. This synthesis supports the inclusion of TRIM26 in candidate gene panels for schizophrenia research.
The overall clinical validity of the TRIM26–schizophrenia association is best classified as Limited according to ClinGen criteria. This rating reflects the reliance on association signals obtained from GWAS meta-analyses of thousands of subjects (e.g. 9,394 cases and 12,462 controls [PMID:22433715]) without robust segregation or de novo variant evidence. Although statistically significant association signals and concordant differential expression data have been reported, the absence of clearly defined causative coding variants reduces the confidence level. Consequently, despite the promising nature of the data, the evidence does not yet reach a higher ClinGen tier. The collective findings warrant cautious interpretation for diagnostic and research applications.
Genetic evidence for TRIM26’s involvement in schizophrenia originates from multi-patient studies that utilize expression QTL and neuroimaging analyses to correlate genetic variants with disease status. The GWAS meta-analysis evaluated over 6,000 SNPs with a significance threshold of <0.001 and identified several cis-acting effects that impacted gene expression in whole blood. However, no direct coding change meeting a full HGVS description – such as a c. variant – was reported for TRIM26. As a result, while TRIM26 is statistically implicated among other MHC region genes, the absence of a clearly defined variant limits the precision of genetic evidence. This genetic association is therefore classified as Limited, with the recognition that large cohorts provide some quantifiable support (PMID:22433715, PMID:24160291). The genetic data encourage further exploration through sequencing and variant-level validation studies.
Functional evidence for TRIM26 largely stems from experimental studies that, while not directly assaying schizophrenia, elucidate its role in critical cellular processes. One study demonstrated that TRIM26 catalyzes the polyubiquitylation of NTH1, a protein involved in base excision repair, thereby modulating cellular responses to oxidative stress (PMID:29610152). Such mechanistic insights are relevant to neuroinflammatory and oxidative pathways that have been proposed to contribute to schizophrenia pathogenesis. In vitro assays confirmed that altered TRIM26 function affects protein stability and the kinetics of DNA repair, offering plausible biological context for its involvement in a multifactorial disorder. Although the functional studies do not provide direct evidence linking TRIM26 dysfunction to schizophrenia phenotypes, they support a model in which TRIM26 regulatory disruption could predispose to neural dysregulation. Overall, this functional data is considered Moderate in strength given its mechanistic clarity even if the link to the clinical phenotype remains indirect.
No significant conflicting data have been presented that refute the TRIM26–schizophrenia association. All available studies, even those focused on related candidate genes or alternative neuroimaging endpoints, converge on the involvement of the MHC region and its regulatory complexity in schizophrenia. The current body of evidence lacks studies that assign alternative phenotypes to TRIM26 in the context of psychiatric conditions. Nonetheless, the indirect nature of the association and the reliance on population-based correlation studies necessitate continued scrutiny and additional replication. As further case-level and familial data become available, the confidence in clinical utility may be reassessed. This balanced view is essential to guide both diagnostic decision-making and potential commercial applications.
In summary, TRIM26 is implicated in schizophrenia based on limited genetic evidence and moderate functional support. Integration of large-scale GWAS data with functional studies on TRIM26’s role in cellular stress response supports its candidacy as a contributory factor in the complex genetic architecture of schizophrenia. While additional variant-level and segregation evidence is needed to elevate the ClinGen classification, the current findings justify the gene’s inclusion in future research and diagnostic panels. Key take‑home: TRIM26 represents a promising yet preliminary candidate gene for schizophrenia, meriting further investigation to enhance clinical utility.
Gene–Disease AssociationLimitedAssociation signals from large-scale GWAS and eQTL studies (e.g. 9,394 cases, 12,462 controls [PMID:22433715]) support a link between TRIM26 and schizophrenia. However, the lack of direct segregation and coding variant evidence limits the classification to Limited. Genetic EvidenceLimitedGenetic evidence is drawn from multi-patient association studies that implicate TRIM26 among other MHC locus genes, but no definitive coding variant (with a full HGVS notation) has been identified to provide higher certainty. Functional EvidenceModerateFunctional studies demonstrate that TRIM26 regulates ubiquitination of proteins such as NTH1, affecting cellular responses to oxidative stress ([PMID:29610152]). This mechanistic insight, while indirect with respect to schizophrenia, supports its potential role in neuroinflammatory pathways. |