Background: A broad region on chromosome 4q was previously linked to the phenotype of alcohol dependence in the Collaborative Study on the Genetics of Alcoholism sample. A strong positional candidate gene was identified within this region: tachykinin receptor 3 gene (TACR3), which encodes tachykinin receptor 3 (NK3R), the receptor for the tachykinin 3 (neurokinin B) peptide. Pharmacological studies have provided evidence that the administration of NK3R agonists attenuates the intake of alcohol and NK3R can also mediate the acute and chronic behavioral effects of cocaine.
Methods: Thirty SNPs were genotyped throughout TACR3. Family based association analysis was performed in 219 European American families to detect an association with alcohol dependence. Subsequent analyses were performed to evaluate the evidence of association with other definitions of alcohol dependence as well as cocaine dependence.
Results: Seven of the 9 SNPs in the 3' region of TACR3 provided significant evidence of association with alcohol dependence (p <or= 0.05). Further analyses suggest that the evidence of association is strongest among those subjects with more severe alcohol dependence (defined by ICD-10) and those with co-morbid cocaine dependence. Haplotype analyses further strengthen the evidence of association in the 3' region of the gene.
Conclusions: These results indicate that sequence variations in TACR3 contribute to the variation in more severe alcohol dependent individuals and those who are also cocaine dependent.