The serotonin-2A receptor gene locus does not contain common polymorphism affecting mRNA levels in adult brain

The serotonin-2A (HTR2A) receptor is a molecule of particular interest in biological psychiatry, as it is an important target for psychotropic drugs,(1,2) and altered HTR2A expression has been found in several neuropsychiatric conditions, including depression(3) and schizophrenia.(4) Genetic association has been reported between a synonymous 102T/C polymorphism in the gene encoding HTR2A and a number of clinical phenotypes, including schizophrenia,(5,6) clozapine response,(7) psychotic symptoms in Alzheimer's disease(8) and certain features of depression.(9) Given that there are no known effects of the 102T/C polymorphism on the structure of the receptor, attention has switched to the possibility that the observations of both altered expression and genetic association point to functional sequence variants that alter expression of the HTR2A gene.(10) Moreover, data have been presented recently suggesting that mRNAs containing the 102T- and C-alleles are differentially expressed.(11) This suggests a direct effect of the variant itself on mRNA levels, or the influence of a distinct regulatory variant, such as the -1438A/G promoter polymorphism, with which it is in perfect linkage disequilibrium.(12) The present study tested this hypothesis by employing a highly accurate quantitative allele-specific primer extension assay(13) to measure the relative expression of brain mRNAs carrying each allele in 23 individuals heterozygous for the 102T/C polymorphism. Comparison between allele ratios derived from genomic DNA and mRNA from several cortical regions revealed that the 102C- and T-alleles are expressed identically. Furthermore, the absence of any interindividual variability in relative mRNA allele ratio suggests that the HTR2A locus is unlikely to contain common polymorphisms or epigenetic modification that alter HTR2A mRNA levels in adult brain, and essentially exclude such phenomena as a potential explanation for the altered expression and genetic associations that have been reported to date.