Identification of four variants in the tryptophan hydroxylase promoter andassociation to behavior

One of the most replicated findings in biological psychiatry is the observa tion of lower 5-hydroxyindoleacetic acid concentrations, the major metaboli te of serotonin, in the brain and cerebrospinal fluid of subjects with impu lsive aggression. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin, however functional variants have not been re ported from the coding sequence of this gene. Therefore, we screened the hu man TPH promoter (TPH-P) for genetic variants which could modulate TPH gene transcription. The TPH-P (2093 nucleotides) was screened for sequence vari ation by SSCP analysis of 260 individuals from Finnish, Italian, American C aucasian, and American Indian populations. Four common polymorphisms were i dentified: -7180T>G, -7065C>T, -6526A>G, and -5806G>T (designated as nucleo tides upstream of the translation start site). In the Finns, the four polym orphisms had a minor allele frequency of 0.40 and in this population linkag e disequilibrium between the four loci was complete. In the other populatio ns the minor allele frequencies ranged from 0.40 to 0.45. TPH -6526A>G geno type was determined in 167 unrelated Finnish offenders and 153 controls pre viously studied for the TPH IVS7+779C>A polymorphism. A significant associa tion was observed between -6526A>G and suicidality in the offenders. TPH -6 526A>G and the previously reported intron seven polymorphism, TPH IVS7+779C >A, exhibited a normalised linkage disequilibrium of 0.89 in Finns. Normali zed linkage disequilibrium was reduced in other populations, being 0.49 and 0.21 in Italians and American Indians, respectively. In conclusion, four T PH-P variants were identified which can be used for haplotype-based analysi s to localize functional TPH alleles influencing behavior.