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Background : The dopamine receptor D4 [ DRD4 ] has been reported to be associated with substance use. Yet, the roles that health conditions and behaviors may play in such association are understudied. Objective : This longitudinal study investigated the potential mediation effects of chronic pain and delinquency in adolescence on the association between the  DRD4  2-repeat allele and substance use in adulthood. Sex, witnessing violence, and experiencing violence were also examined as potential moderators for the mediation pathways. Methods : We used the restricted and candidate gene data from the National Longitudinal Study of Adolescent to Adult Health (Waves I–IV) to conduct secondary analysis ( N  = 8,671; 47% male). A two-step approach was adopted to examine the mediation effects regarding four substance use outcomes in adulthood: number of lifetime alcohol use disorder symptoms, lifetime regular smoker status, past-month smoking, and lifetime “pain killer” misuse. The moderation effects were investigated using stratification and permutation. Results : The  DRD4  2-repeat allele was associated with all adulthood substance use outcomes through adolescent chronic pain and delinquency (AORs/IRR range 1.08–3.78; all  p s&lt;0.01). The association between delinquency and smoking was higher among females. The association between delinquency and substance use was lower among the participants who witnessed violence in adolescence. Conclusions : This study identified modifiable mediators underlying the association between the  DRD4  2-repeat allele and substance use behaviors, concluding that chronic pain and delinquency partially explain the effect of the  DRD4  gene polymorphism on adult substance use.

Chronic pain and delinquency partially explain the effect of the DRD4 gene polymorphism on adult substance use