Association between T102C and A-1438G polymorphisms in the serotonin receptor 2A (5-HT2A) gene and schizophrenia:: relevance for treatment with antipsychotic drugs

Background: An involvement of serotonin receptor 2A (5-HT2A) in the aetiology of schizophrenia has been hypothesised. The 5-HT2A receptor also appears to be an important site of action of atypical antipsychotic drugs. Indeed, association between schizophrenia and the T102C silent polymorphism of the 5-HTR2A gene has been reported. Another polymorphism in the promoter region of 5-HTR2A (A-1438G) in linkage disequilibrium with the T102C polymorphism has also been reported. It has been suggested that the A-1438G polymorphism alters promoter activity and expression of 5-HT2A receptors and might be responsible for the associations with schizophrenia and the efficacy of atypical antipsychotics such as risperidone. Methods: We analysed the 5-HTR2A T102C and A-1438G polymorphisms in clinically stable schizophrenia patients (SPs) and healthy volunteers (HVs). We developed an allele-specific PCR-based restriction fragment length polymorphism (PCR-RFLP) method. In SPs, we also described differences across both diagnosis subtypes (paranoid vs. non-paranoid) and antipsychotic drug treatment (risperidone vs. other classical antipsychotic drugs). Results: Two groups of 114 SPs and 142 HVs were studied. The frequency of the 5-HTR2A-1438A allele was higher in SPs than in HVs (0.54 vs. 0.44; p < 0.05). The frequency of the 102T allele was also higher among SPs than HVs (0.56 vs. 0.46; p < 0.05). These two polymorphisms were in linkage disequilibrium. The percentage of carriers of the 1438A/A and 102T/T alleles was 26% and 15% for SPs and HVs, respectively (p < 0.05; odds ratio 1.9). No differences in genotype or allele frequencies were found between paranoid and non-paranoid SPs or between SPs on risperidone and those on classical antipsychotic treatment. Conclusions: The present study demonstrates a higher frequency of 5-HTR2A-1438A and 102T alleles in SPs compared to HVs.