Genetic polymorphisms, DNA methylation and antipsychotic induced weight gain in schizophrenia patients.

Antipsychotic drug-induced weight gain is a common adverse effect of antipsychotic medication in patients with schizophrenia. Many factors including genetic and environmental factors may contribute to this adverse effect. The antipsychotic drugs and genetic factors may influence the weight gain through epigenetic mechanisms, including DNA methylation. The aim of this study was to investigate the associations of antipsychotic drug-induced weight gain with genetic polymorphisms and DNA methylation of HTR2C. In addition, the aim of this study was to investigate the effect of antipsychotic drug treatment on DNA methylation and mRNA expression of HTR2C and on leptin secretion by adipocytes.DNA samples from both first episode drug n ive and chronic schizophrenic patients were genotyped using TaqMan SNP Genotyping Assays and the extent of DNA methylation was measured using bisulfite pyrosequencing. The MTHFR rsl801133 genetic polymorphism was significantly associated with BMI change in first episode drug na ive Chinese Han and Spanish patients. In Chinese Han cohort, a significant association was also found of the MC4R rs489693 with BMI change. In addition, when patients were analysed as group receiving either risperidone or chlorpromazine, a significant genotype-drug interaction was observed with the HTR2A rs6311, and also found significant associations between the HTR2A rs6311 and ADRA2A rs1800544 with risperidone-induced weight gain.Global DNA methylation was measured by determining methylation of LINE-1 in chronic schizophrenia patients. Results show no significant association of LINE-1 methylation with BMI, although the MTHFR rs1801133 and FTO rs9939609 SNPs had significant influence on LINE-1 methylation in this cohort. DNA methylation levels of the HTR2C promoter sequence were also measured. The extent of DNA methylation of the HTR2C promoter sequences in samples taken before patients received antipsychotics was significantly higher in Chinese Han patients who subsequently had weight increase <7%; therefore, DNA methylation of the HTR2C promoter sequences may be a predictor for antipsychotic drug-induced weight gain in drug na ive patients. In addition, the T allele of the HTR2C rs3813929 polymorphism was significantly associated with higher methylation of the HTR2C promoter sequence. This provides a mechanistic link between the HTR2C rs3813929 SNP and promoter activity. The FTO rs9939609 SNP was significantly associated with DNA methylation of the HTR2C promoter sequences in Spanish male patients. In chronic patients, DNA methylation of the HTR2C promoter sequence was not significantly associated with BMI; however, it was significantly associated with the HTR2C rs3813929.The effect of antipsychotic drugs on the HTR2C methylation, mRNA expression, and leptin secretion were studied in cell culture models. Clozapine and haloperidol treatment in SH-SY5Y neuroblastoma cells show no significant change DNA methylation and mRNA expression of the HTR2C. In 3T3-L1 adipocytes treated with clozapine, SB 242084, risperidone, and haloperidol show no significant changes in Htr2c mRNA expression and leptin secretion.The associations of genetic polymorphisms and DNA methylation of the HTR2C with antipsychotic drug-induced weight gain may indicate the underlying mechanisms and also provide genetic and epigenetic markers for antipsychotic drug-induced weight gain.