Functional consequences of two HTR2C polymorphisms associated with antipsychotic-induced weight gain

Area of Science:

• Pharmacogenomics
• Molecular Psychiatry
• Neuroscience

Background:

• Genetic variations in the HTR2C gene promoter are linked to antipsychotic-induced weight gain.
• Previous studies explored regulatory potential of these variants using gene-reporter systems.
• Identifying causal variants is key to understanding molecular mechanisms of phenotypic variation.

Purpose of the Study:

• To investigate the binding of nuclear factors to HTR2C polymorphisms rs3813929 and rs518147 using electromobility shift assays.
• To examine allele-specific RNA folding for the rs518147 polymorphism.

Main Methods:

• Electromobility shift assays (EMSA) were used to analyze nuclear factor binding to HTR2C promoter polymorphisms.
• RNA folding was assessed for allele-specific effects of rs518147.
• Nuclear factors from rat hypothalamus were utilized.

Main Results:

• Both HTR2C polymorphisms (rs3813929 and rs518147) demonstrated binding to nuclear factors, confirming their role as regulatory elements.
• The rs3813929 (-759C/T) polymorphism altered DNA-protein interactions; the weight gain-resistant allele abolished two complex formations.
• Allele-specific RNA loop formation was observed for the rs518147 polymorphism.

Conclusions:

• The rs3813929 (-759C/T) polymorphism is functionally significant, impacting DNA-protein interactions.
• Disruption of DNA-protein interactions by HTR2C variants may perturb gene expression.
• This mechanism offers insight into how HTR2C influences antipsychotic-induced weight gain.