Objective: Genes encoding molecular pathways of the reward system are implicated in both addiction and impulsivity. A complex interplay of these genes is likely to contribute to the risk and perpetuation of addiction, both directly and indirectly, mediated via the intermediate phenotype of impulsivity. Methods: We applied different analytic strategies based on direct, indirect, mediation, and epistatic associations to previously reported and/or functionally relevant candidate variants to explore the biological plausibility of their associations and increase the chances of revealing subtle polygenetic effects. We assessed nineteen candidate polymorphisms of the GABA, opioid and dopamine systems in an ethnically distinct and homogenous population sample of 157 Sinhalese male dependent heroin users and 155 age-and ethnicity-matched controls with no lifetime drug use and negligible nicotine or alcohol consumption on a range of association models. Results: GABRA6-rs3219151 and GABRG2-rs211013 showed associations with heroin dependence under a recessive and dominant model respectively. GABRG2-rs211014 and rs211013 showed a haplotype association; mediation analysis showed the association of these two SNPs with heroin dependence being mediated via fun-seeking personality trait and DRD2-rs1079597 mediated via reward sensitivity. OPRM1-rs1799971 and OPRM1-rs563649 were significantly associated with heroin dependence under a multiplicative model. Using generalized multi-dimensionality reduction, we found significant epistatic interaction between GABRG2-rs211013 and OPRM1-rs1799971 and also between these two SNPs and COMT-rs4680 for risk of heroin dependence. Conclusion: These findings portray novel and plausible potential mechanisms of genetic predisposition to heroin dependence.