The 5' region of the tryptophan hydroxylase gene: mutation search and association study with alcoholism

A deficiency in the serotonergic system has been suggested as a negative reinforcer in alcoholism. Tryptophan hydroxylase (TPH) is critical in the fine-tuning of serotonergic neurotransmission. We observed a significantly high frequency of the A allele of the IVS7+218A>C polymorphism in intron 7 of the TPH gene in Japanese alcoholics with histories of drinking-related antisocial behaviors compared with that of Japanese controls (p = 0.006). However, this polymorphism is intronic, and a study of TPH mRNA did not detect aberrant splice products or polymorphic nucleotides linked to this polymorphism. Therefore, we screened for variations in the promoter and 5'-untranslated region of the gene. Three novel variants/polymorphisms, -1066G>A in the 5' flanking region, IVS1B+23(GTTTT)4-5 in intron 1B, and IVS1C+50T>C in intron 1C, were identified. The -1066G>A and IVS1C+50T>C polymorphisms were in modest linkage disequilibrium with the IVS7+218A>C polymorphism. However, no significant association was found between the three novel polymorphisms and alcoholism. Although our findings reiterate that TPH may play some role in the genetic predisposition to alcoholism, the mechanism remains unknown.