Differential expression of the C and T alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics

A genetic association between schizophrenia and a silent C/T(102) polymorphism in the 5-HT2A receptor gene (5-HT2AR) has been previously reported; however, the mechanisms underlying this association remain unknown. Here we developed an improved quantitative assay for measurements of allele ratios, which revealed that the expression of allele C in the temporal cortex of normal heterozygous individuals was significantly lower than the expression of allele T (allele C to allele T ratio of similar to0.8, P < 0.0001). Confirming decreased expression of allele C, total levels of 5-HT2AR mRNA and protein in normal individuals with the C/C genotype were lower than in individuals with the T/T genotype. Similarly to normal individuals, allele C to allele T ratio in heterozygous schizophrenics was reduced (similar to0.8, P < 0001). This ratio was independent of neuroleptic treatment history. By contrast, total levels of 5-HT2AR mRNA correlated inversely with neuroleptic free interval prior to death (r = -0.67, P < 0.001) suggesting a reversible neuroleptic effect. Total levels 5-HT2AP mRNA in neuroleptic free (> 26 weeks) schizophrenics (n = 11) were significantly lower than in controls (P = 0.03). The data suggest that increased prevalence of allele C among schizophrenics may be due to intrinsically low expression of this allele, which may contribute to a deficit in 5-HT2AR expression in some schizophrenics. Published 2002 Wiley-Liss, Inc.