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Identification of a psychiatric risk gene NISCH at 3p21.1 GWAS locus mediating dendritic spine morphogenesis and cognitive function

Summary

Researchers identified a gene called NISCH that increases the risk of schizophrenia and bipolar disorder. When this gene is overactive, it changes the shape of connections between brain cells and impairs working memory in mice. Interestingly, blood pressure medications like clonidine can reduce NISCH activity and improve cognitive function, suggesting these drugs might help psychiatric patients.

Background

Schizophrenia and bipolar disorder share clinical symptoms, genetic risk factors, and pathogenic mechanisms. Previous studies identified a GWAS locus at 3p21.1 showing significant associations with both disorders, with a risk SNP rs2251219 in linkage disequilibrium with a human-specific Alu polymorphism rs71052682 that demonstrated enhancer effects.

Objective

To identify genes at the 3p21.1 GWAS locus directly affected by the Alu polymorphism rs71052682 and characterize their physiological impacts on dendritic spine morphogenesis and cognitive function in psychiatric disorders.

Results

Deletion of the Alu sequence reduced NISCH mRNA expression in cell lines. NISCH expression was elevated in brain tissues of psychiatric patients. Overexpression of NISCH decreased mushroom dendritic spine density and increased thin spine density in neurons, and impaired spatial working memory in mice. Antihypertensive drugs clonidine and tizanidine reduced NISCH expression and rescued cognitive impairment.

Conclusion

NISCH is identified as a psychiatric risk gene at the 3p21.1 GWAS locus that mediates dendritic spine morphogenesis and cognitive function. Nischarin, the protein encoded by NISCH, represents a potential therapeutic target for psychiatric disorders through antihypertensive agents.
  • Published in:BMC Medicine,
  • Study Type:Molecular and Behavioral Research Study,
  • Source: PMC10347724, PMID: 37443018
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