Rs6314

Abstract: Serotonin receptor 2A (HTR2A) is an important signalling factor implicated in cognitive functions and known to be associated with schizophrenia. The biological significance of HTR2A in schizophrenia remains unclear as molecular analyses including genetic association, mRNA expression and methylation studies have reported inconsistent results. In this study, we examine HTR2A expression and methylation and the interaction with HTR2A polymorphisms to identify their biological significance in schizophrenia. Subjects included 25 schizophrenia and 25 control post-mortem brain samples. Genotype and mRNA data was generated by transcriptome sequencing. DNA methylation profiles were generated for CpG sites within promoter-exon I region. Expression, genotype and methylation data were examined for association with schizophrenia. HTR2A mRNA levels were reduced by 14% (p = 0.006) in schizophrenia compared to controls. Three CpG sites were hypermethylated in schizophrenia (cg5 p = 0.028, cg7 p = 0.021, cg10 p = 0.017) and HTR2A polymorphisms rs6314 (p = 0.008) and rs6313 (p = 0.026) showed genetic association with schizophrenia. Differential DNA methylation was associated with rs6314 and rs6313. There was a strong correlation between HTR2A DNA methylation and mRNA expression. The results were nominally significant but did not survive the rigorous Benjamini-Hochberg correction for multiple testing. Differential HTR2A expression in schizophrenia in our study may be the result of the combined effect of multiple differentially methylated CpG sites. Epigenetic HTR2A regulation may alter brain function, which contributes to the development of schizophrenia.

Abstract: OBJECTIVE The serotonin 2A receptor gene (HTR2A) is involved in serotonergic neurotransmission, and has been targeted as a functional candidate for mood disorders because of the extensive support for the involvement of serotonin in mood regulation. We previously reported linkage evidence for a bipolar affective disorder susceptibility locus on chromosome 13q, which harbours HTR2A, thus making the gene both a positional and functional candidate. We assessed HTR2A for association in an Australian bipolar disorder case-control cohort. METHODS Single nucleotide polymorphisms (SNPs) were selected across HTR2A exons and introns, and were investigated for association in an Australian cohort of 218 cases and 166 healthy controls. SNP haplotypes were also examined for association. RESULTS Significant association of rs2224721 (P = 0.02) and borderline significance of rs1923886 (P = 0.05) were observed. The former remained significant after multiple testing corrections using the rough False Discovery Rate method, but did not exceed the more conservative Bonferroni's correction threshold. Haplotype association analysis suggests that the haplotype CCGCA (at SNPs rs3125, rs6314, rs1923886, rs2224721 and rs2770296) is protective against bipolar disorder (P = 0.021, odds ratio 0.63) and the rarer haplotype CCACG confers risk to the disorder (P = 0.0065, odds ratio 3.08). CONCLUSION We found that HTR2A is associated with bipolar disorder. The HTR2A gene should not be excluded as a potential susceptibility gene for bipolar disorder despite a number of conflicting association results.

Abstract: Objective Genetic polymorphisms and mutations in candidate genes are considered important in the etiology of autism, and particular interest is focussed on the serotonin system. Here, we used SNP analysis in the serotonin receptor gene to identify differences between autistic and healthy control children. Methods Genetic association of rs6313 (T102C) and rs6314 (C1354T) polymorphisms in HTR2A gene with susceptibility to the development of autism in children were investigated using PCRRFLP, and correlated serotonin levels in blood serum using ELISA method. Results We uniquely found an association between the presence of the T allele at the position rs6313 (OR=2.00, 95%CI: 1.23-3.26, p=0.005), and between the presence of the C allele at the position rs6314 (OR=2.24, 95% CI: 1.47-3.42, p=0.0002) of the serotonin receptor gene under conditions of a decreased ASD incidence. We also noted that T allele at the position rs6313, and C allele at the position rs6314 was 3 times more frequent in Control males than in ASD males. We found no statistical significant correlation between HTR2A SNPs and the blood serum level of serotonin between autistic and control children. Conclusion This study shows the involvement of HTR2A, rather than the concentration of serotonin, in the development of autism, and provides a rationale for future design of therapeutic modalities based on the serotonin system for childhood autism.