Genetic factors may contribute to alcoholism. CSF 5-HIAA, the principal metabolite of serotonin, can identify individuals with a deficit of CNS serotonin metabolism. Decreased serotonin metabolism, as indicated by low CSF 5-HIAA, is postulated to be connected with behaviors characterized by deficient impulse control. 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-HT1A receptor which, in part, regulates serotonergic activity. The human TPH gene was mapped to chromosome 11p15.5. A human TPH variant, in intron 7, associated with CSF 5-HIAA concentration in alcoholic, impulsive, Finnish violent offenders. The variant associated with a history of suicidal attempts and of multiple suicidal attempts in alcoholic, violent Finns. The variant TPH alleles have been sequenced. Splicing of intron 7 occurs accurately. Three additional TPH variants have been identified and are being characterized. Additional studies are underway to replicate the association of the TPH intron 7 variant and suicidality. Three variants of the human 5-HT1A gene have been identified by 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 stably expressed in CHO-K1 cells 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. We are studying the relationship of the vervet variant to CSF 5-HIAA and prosocial behaviors.
