Identification and analysis of new sequence variants in the human tryptophan hydroxylase (TpH) gene

The tryptophan hydroxylase (TpH) gene codes for the rate-limiting enzyme in serotonin biosynthesis. It is one of the major candidate genes for psychia tric and behavioral disorders. A polymorphism in TpH intron 7 has been show n to be associated with suicidal attempts, aggressive behavior and psychiat ric illnesses. By systematically screening the TpH genomic sequence, we ide ntified and confirmed an earlier report of four Variants in the promoter re gion and localized six new sequence variants, ie two in intron 1b, one in e xon 1c, one in intron 8, one in intron 9 and a microsatellite in the 3' reg ion, 5687 bp downstream of the last exon 11. We analyzed these polymorphism s, as well as the one in intron 7, by Single Strand Conformation Analysis, microsatellite or restriction analysis in a collection of 175 West European Caucasian healthy subjects. The four Variants in the promoter region are i n complete linkage disequilibrium (frequencies of G-T-G-T and T-C-A-G haplo types are 0.41 and 0.59, respectively). Deletion of GTT in intron 1b is rar e (0.7%) and so not informative. The rarer allele T of intron 1b polymorphi sm T3792A has a frequency of 0.34 and is in partial linkage disequilibrium with the more common alleles of intron 7, 8 and 9. The polymorphisms of the se three introns are in complete linkage disequilibrium and the frequencies of haplotypes A-T-C and C-C-T are 0.36 and 0.64 respectively. We detected 10 different alleles in the microsatellite localized in the 3' region; alle le '194' is in partial linkage disequilibrium with haplotype A-TC of intron s 7, 8, and 9. Analysis of these different polymorphisms will constitute an important toot for future studies between the TpH gene and psychiatric dis orders.