A Role for the DRD4 Exon III VNTR in Modifying the Association Between Nicotine Dependence and Neuroticism

Neurotic psychopathology has been extensively examined as a risk factor for nicotine dependence (ND). Genetic stratification may partially explain variability in risk estimates. Genetic variants that compromise dopaminergic neurotransmission may motivate exposure to dopamine-stimulating agents, including nicotine. The 7-repeat allele of a Variable Number Tandem Repeat (VNTR) polymorphism in DRD4 (and evolutionary derivatives 5, 6, and 8 repeats; 7R+) is associated with reduced dopamine receptor function. The purpose of this study was to examine association between both smoking initiation (SI) and progression to ND by young adulthood and (a) history of neuroticism during adolescence, (b) DRD4 7R+, and (c) interaction between neuroticism and DRD4 7R+. Participants were drawn from the Victorian Adolescent Health Cohort Study, a longitudinal study of the health and well-being of young Australians across 8 waves (14-24 years). Neuroticism was measured at Waves 3 and 6 (mean 15.9 and 17.4 years). SI was defined as any smoking at any wave. ND was measured at Wave 8 (mean 24.1 years). Genotype data for the DRD4 VNTR were available for 839 participants. While adolescent neuroticism was associated with SI, evidence for association with progression to ND was weak. However, there was evidence of interaction between neuroticism and DRD4 7R+: The odds of progression to ND among those with a history of neuroticism were more than 3.5-fold higher among 7R+ carriers. Without considering stratification by 7R+, the association between progression to ND and neuroticism would have been assumed barely significant. However, among those carrying DRD4 7R+, risk of progression was considerably intensified.