Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder

Introduction: HTR2A gene has been the subject of numerous studies in psychiatric genetics because LSD, which resembles serotonin causes psychosis and atypical antipsychotic drugs target the HTR2A receptor. However, evidence for the role of HTR2A polymorphism(s) in schizophrenia (SCZ) and bipolar disorder (BD) has been elusive. We hypothesized that epigenetic dysregulation of HTR2A may be involved in psycho-pathogenesis and analyzed promoter DNA methylome and expression of HTR2A in SCZ, BD and control subjects. Method: DNA derived from post-mortem brains of patients with SCZ and BD and matched control subjects (each 35) were obtained from the Stanley Medical Research Institute. While bisulfite DNA sequencing was used to screen and quantify cytosine methylation in the HTR2A promoter, corresponding gene expression was analyzed by qRT-PCR. Results: We found strong evidence for epigenetic fine-tuning of HTR2A expression. In general, the expression of HTR2A in individuals carrying the C allele of T102C (or G allele of -1438A/G polymorphism) was higher than TT genotype. Interestingly, promoter DNA of HTR2A was hypermethylated at and around the -1438A/G polymorphic site, but was hypomethylated at and around T102C polymorphic site in SCZ and BD compared to the controls. Furthermore, epigenetic down-regulation of HTR2A was associated with early age of disease onset in SCZ and BD. Conclusion: Epigenetic dysregulation of HTR2A may contribute to SCZ, BD and earlier age of disease onset. Further research is required to delineate the dysregulation of other components of serotoninergic pathway to design new therapeutics based on the downstream effects of serotonin.