MOLECULAR STUDIES ON GENETIC VARIANTS OF TRYPTOPHAN HYDR

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Cerebral spinal fluid (CSF) 5-HIAA, the principal metabolite of serotonin, can identify individuals with a deficit of central nervous system serotonin metabolism. Decreased serotonin metabolism, as indicated by low CSF 5-HIAA, is postulated to be connected with behaviors characterized by deficient impulse control including alcoholism. Trait differences in CSF 5-HIAA concentration may be due to genetic variants of genes regulating serotonin metabolism. To identify factors controlling serotonin-dependent behaviors, we have focused our efforts on tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin, and the 5-HT receptor which, in part, regulates serotonergic activity. A variant, the first in TPH, was identified and used to map the human TPH gene to chromosome 11p15.5 The variant, which is in intron 7 of TPH, was found to be associated with CSF 5-HIAA concentration in alcoholic, impulsive, Finnish offenders. The variant associated with a history of suicidal attempts and of multiple suicidal attempts in alcoholic Finnish offenders. This finding of an association of the TPH variant with suicidal behavior has been replicated in a new population of Finnish alcoholic offenders. Evidence for linkage of TPH was found to alcoholism, suicidality, and KSP socialization score. In other studies, an association of TPH genotype with suicidality in depressed patients and to impulsive-aggressive behavior in personality disorder patients was found. TPH cDNA was sequenced from individuals homozygous for both alleles and no alteration in mRNA splicing was observed. Nearly the entire coding region of the TPH gene has been analyzed and only one rare silent variant was found. Analysis of the upstream sequences have identified three additional variants. These have been fused to a reporter gene and are being analyzed. EMSA analysis revealed differential binding of factors to the variant alleles. Three variants of the human 5-HT1A gene have been identified by single-strand conformational polymorphism (SSCP) analysis. Two variants change the protein sequence and the third is silent. The Ser22 variant in the extracellular amino-terminus of the human 5-HT1A receptor decreases agonist-promoted down-regulation and desensitization of receptor expression. In addition, an allelic variant has been identified in the 5-HT1A gene in vervet monkeys.