Background: The -1438A/G single nucleotide polymorphism (SNP) lies just upstream of two alternative promoters for the 5-hydroxytryptamine type 2A (5-HT2A) receptor gene (HTR2A) and is in strong linkage disequilibrium with the 102T/C SNP. Both SNPs are associated with numerous psychiatric disorders and related phenotypes. A possible functional affect of the -1438A/G SNP might underlie associations of both linked SNPs with these neuropsychiatric disorders. A prior investigation into affects of this SNP on promoter function, lacking the more downstream promoter, found no significant difference with a reporter gene assay.
Methods: To investigate possible functional effects of -1438A/G on either promoter, two different reporter gene assays were used in three cell lines.
Results: Promoter activity was consistently detected that, in the presence of the SV40 enhancer, was significantly greater in the presence of the A allele relative to the G allele but only in cell lines that express endogenous HTR2A, suggesting that transcriptional factor(s) and the presence of both promoters might be necessary to elicit this effect.
Conclusions: These findings show that the -1438A/G SNP has the potential to modulate HTR2A promoter activity and might be the functional variant responsible for the associations of both SNPs with many neuropsychiatric phenotypes.