A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identification of new polymorphisms in the promoter.

Several studies have shown an association between schizophrenia and the C allele of a T-C polymorphism at nucleotide 102 and the 5HT2A receptor gene. In the present study we observed this association in a sample of 63 parent/offspring trios where the proband received a diagnosis of DSM-III-R schizophrenia using TDT analysis (chi2 = 6.26, P= 0.006, chi2 = 9.00, P=0.001 when one affected offspring was selected at random from each family, suggesting that the results are due to association rather than linkage). There was no significant difference between the transmission of C102 from heterozygous fathers and mothers, which fails to support a role for genomic imprinting in this effect. T102C does not result in an alteration of the amino acid sequence of the protein. We therefore screened the promoter of 5HT2A for polymorphisms using single-strand confirmation polymorphism analysis. An A-G polymorphism at -1438 that creates an HpaII restriction site was identified. This was found to be in complete linkage disequilibrium with T102C and is hence a candidate for the pathogenic variant in schizophrenia. Functional analysis of A-1438G using luciferase assay demonstrated significant basal promoter activity in 5HT2A expressing HeLa cells by both the A and G variants. However, comparison of the A and G variants showed no significant differences in basal activity nor when promoter activity was induced by cAMP and protein kinase C-dependent mechanisms.