SLC18A2 – Schizophrenia

Candidate gene studies have reported associations between common SLC18A2 (VMAT2) polymorphisms and Schizophrenia susceptibility and related neurocognitive deficits. In a cohort of 718 patients, rs363227 in SLC18A2 was linked to increased schizophrenia risk (OR = 1.51) and impacted cognitive performance (PMID:22532702). A north Indian sample of 601 case–parent trios yielded nominal associations of SLC18A2 SNPs (rs363399, rs10082463) with schizophrenia and executive function measures, although these findings did not withstand multiple correction (PMID:23932573). A Han Chinese study of 430 patients and 470 controls found no overall association for rs363371 and rs363324, but identified a male-specific protective effect of the rs363371 AA genotype (OR = 0.56) in males (PMID:33099987).

Functional promoter analyses demonstrated that specific SLC18A2 haplotypes alter VMAT2 expression by ~20%, defining alleles that confer protection against alcoholism; however, their direct impact on schizophrenia has not been tested (PMID:15829504).

Despite biological plausibility linking VMAT2-mediated monoamine vesicular storage to schizophrenia pathophysiology, the limited number of probands, absence of segregation data, and inconsistent replication across populations support a Limited level of clinical validity for the SLC18A2–schizophrenia association. Additional well-powered genetic studies and functional assays in neural systems are required.

Key Take-home: Current evidence for SLC18A2 as a schizophrenia risk gene is limited and not yet sufficient for clinical application.

References

• Schizophrenia Bulletin • 2013 • Intermediate phenotype analysis of patients, unaffected siblings, and healthy controls identifies VMAT2 as a candidate gene for psychotic disorder and neurocognition. PMID:22532702
• Journal of psychiatric research • 2013 • Dopaminergic gene polymorphisms and cognitive function in a north Indian schizophrenia cohort. PMID:23932573
• Psychiatry Investigation • 2020 • The Gene Polymorphism of VMAT2 Is Associated with Risk of Schizophrenia in Male Han Chinese. PMID:33099987
• Human molecular genetics • 2005 • SLC18A2 promoter haplotypes and identification of a novel protective factor against alcoholism. PMID:15829504

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