To identify genetic contributions to alcoholism vulnerability, we focused on serotonergic behaviors, since a subtype of alcoholism is associated with decreased serotonin turnover. Serotonin biosynthesis is governed by tryptophan hydroxylase (TPH), which is rate-limiting. We hypothesize that genetic variants of TPH and TDO and factors controlling their gene expression play a major role in behavior. We cloned and sequenced the cDNA and gene for murine TPH gene. The human TPH gene was mapped to chromosome 11p15.5. The human TPH polymorphism associated with CSF 5-HIAA concentration in alcoholic, impulsive, Finnish violent offenders. The polymorphism associated with history of suicidal attempts and of multiple suicidal attempts in alcoholic, violent Finns. The polymorphic TPH alleles are being sequenced. The factors and DNA sequences controlling the expression of the mouse TPH gene are being identified. DNA regions controlling tissue-specific and constitutive expression have been identified using DNA fusion constructs. These regions are being analyzed by electrophoretic mobility shift analysis to identify transcription factors and their cognate binding sites that regulate TPH gene expression. RBP- Jk was found to negatively regulate TPH gene expression. We have cloned the RBP-Jk and it is being characterized.
