Hypomethylation of the serotonin receptor type‐2A Gene (HTR2A) at T102C polymorphic site in DNA derived from the saliva of patients with schizophrenia and bipolar disorder

Abstract

Several lines of evidence indicate that dysfunction of serotonin signaling and HTR2A receptor are involved in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BD). DNA methylation of HTR2A at T102C polymorphic site influences HTR2A expression and aberrant DNA methylation of HTR2A promoter was reported in postmortem brain of patients with SCZ and BD. Hypothesizing that the brain's epigenetic alteration of HTR2A may also exist in peripheral tissues that can be used as a diagnostic/therapeutic biomarker, we analyzed HTR2A promoter DNA methylation in DNA extracted from the saliva of patients with SCZ and BD, and their first degree relatives versus normal controls. Bisulfite sequencing was used to screen DNA methylation status of the HTR2A promoter CpGs and qMSP was used to quantify the degree of cytosine methylation at differentially methylated sites. Most of the cytosines of the HTR2A promoter were unmethylated. However, CpGs of the -1438A/G polymorphism site, -1420 and -1223 were >95% methylated. The CpG at T102C polymorphic site and neighboring CpGs were ∼70% methylated both in the patients and controls. qMSP analysis revealed that the cytosine of the T102C polymorphic site was significantly hypo-methylated in SCZ, BD, and their first degree relatives compared to the controls. Cytosine methylation of HTR2A at T102C polymorphic site in DNA derived from the saliva can potentially be used as a diagnostic, prognostic, and/or therapeutic biomarker in SCZ and BD. However, these preliminary observations need to be replicated in other populations with a larger sample size to be considered for clinical applications.

Fibromyalgia: A Critical and Comprehensive Review

“…Note that the T102C SNP in the HTR2A gene is part of a methylation site that influences the expression of this serotonin receptor. Therefore, some of the discrepant findings concerning the association of this SNP with FMS (see Table 5) may arise from differential methylation and gene expression in carriers of the C allele [478]. In a pilot study, it was recently shown that the genome-wide methylation pattern differed significantly between women with FMS and healthy controls [479].…”

Reviewing the epigenetics of schizophrenia

“…A handful of studies were epidemiological (e.g. Nazarova, 1996), whilst others used methods including saliva samples (Ghadirivasfi et al, 2011), GWAS and and not available to the same degree across subjects -D. A. Lewis, 2002).…”

“…Benes et al, 2007;Carrard, Salzmann, Malafosse, & Karege, 2011;Ghadirivasfi et al, 2011). Others investigated brain features such as cerebellar weight and pre-frontal cortex variations, levels of methylation in brain or blood tissues, associations between epigenetic processes and smoking, age, medication use and physical activity, studies of x-chromosome linkage, and paternal age and its association with schizophrenia diagnoses (e.g.…”

Research Highlights: Epigenetic changes to serotonin receptor gene expression in schizophrenia and bipolar disorder

“…Polymorphisms in the genes encoding these receptors are considered good candidates for mediating susceptibility to psychosis, and they have been widely studied in genetic association studies [4]. Recently, increasing emphasis has been placed on the potential role of epigenetic dysfunction in the etiology of psychosis [5,6], and converging evidence suggests that epigenetic factors are important in the regulation of serotonin receptor gene expression [7][8][9].…”