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TSNARE1 has emerged as a candidate gene for schizophrenia through multiple lines of evidence derived from case–control studies and family‐based sequencing. A initial study in a Han Chinese population demonstrated that common TSNARE1 polymorphisms were significantly associated with schizophrenia risk in a cohort comprising 440 patients and 450 control subjects (PMID:25471352). This study identified an association under a recessive genetic model, wherein the homozygous state for the minor allele was linked to a decreased risk of disease. The reported findings provide an important context for understanding the genetic architecture underlying schizophrenia.
Genetic evidence further comes from a family‐based whole exome sequencing study in 65 Han Chinese families where TSNARE1 was among several candidate susceptibility genes. In this study, analyses of 51 trios revealed de novo and compound heterozygous mutations in multiple genes, including TSNARE1 (PMID:32066673). Although detailed segregation counts of affected relatives were not reported explicitly for TSNARE1, the replication of its involvement across family‐based and case–control studies strengthens the overall genetic support for its association with schizophrenia.
The case–control study provided robust statistical evidence with significant odds ratios and a recessive inheritance pattern for the protective minor allele, suggesting that genetic variation in TSNARE1 contributes to schizophrenia risk. The investigation further highlighted that the association rests on common polymorphisms, with the recessive model (A/A versus A/C + C/C) being most informative. Moreover, the consistency of the findings across different population groups adds to the credibility of TSNARE1 as a susceptibility gene.
While a detailed variant spectrum including HGVS‐formatted coding variants was not explicitly provided in the evidence, two single nucleotide polymorphisms (rs10098073 and rs4129585) have been a focus. Due to the absence of a conventional coding change described in HGVS nomenclature within the supplied evidence, the list of reported HGVS variants remains empty. This does not detract from the overall genetic signal observed at the TSNARE1 locus.
Functional studies have provided moderate support for the regulatory involvement of the TSNARE1 locus in schizophrenia. Two independent functional assessments investigated a variant near TSNARE1 (rs4129585), demonstrating that the risk allele drives altered reporter expression in zebrafish neuronal populations and elicits significant transcriptional differences in neural progenitor cells derived from human induced pluripotent stem cells (PMID:38187620; PMID:38702885). These experiments linked the variant not to TSNARE1 transcript levels but to effects on neighboring regulatory elements, implying a role in synaptogenesis and axon guidance. Such evidence, while indirect regarding TSNARE1 expression, is consistent with a pathogenic mechanism that contributes to disease risk.
Notably, some functional data also point to the involvement of nearby genes such as ADGRB1; however, the genetic findings specific to TSNARE1 remain robust. There is no compelling conflicting evidence that refutes TSNARE1’s association with schizophrenia, even though the complexity of the locus invites further investigation into gene–gene regulatory networks. The converging evidence makes a strong case for TSNARE1 as an important susceptibility locus.
In conclusion, the integration of multi‐patient genetic studies with functional assays supports a strong association between TSNARE1 (HGNC:26437) and schizophrenia (MONDO_0005090). The association is backed by significant case–control data, family‐based replication, and functional investigations that underscore a regulatory mechanism linked to synaptic pathways. These findings provide a solid basis for incorporating TSNARE1 into diagnostic decision‐making and further research into the molecular etiology of schizophrenia.
Gene–Disease AssociationStrongCase–control data from 440 patients (PMID:25471352) and replication in 65 familial trios (PMID:32066673) support a strong association. Genetic EvidenceStrongMultiple independent studies including a robust case–control study and family-based sequencing provide compelling genetic evidence. Functional EvidenceModerateFunctional assays in zebrafish and human iPSC–derived neural progenitor cells (PMID:38187620; PMID:38702885) demonstrate regulatory effects relevant to synaptic function. |