It is important to note that some functional and neurobiological findings have been interpreted as indicating that the G allele of rs1799971 should increase risk for addiction, for example due to its association with greater alcohol-induced reinforcement and reward (Ramchandani et al. 2011; Ray and Hutchison 2004; Ray and Hutchison 2007; Ray et al. 2010). Our data-driven evidence of a modest protective effect of this allele on substance dependence liability is thus surprising and all the more important to integrate with functional findings to understand downstream contributions to human substance dependence. A protective effect of the G allele on addiction may be consistent with either increased or decreased reward/reinforcement, for example due to varying roles of positive versus negative reinforcement at different stages in the transition from use to dependence. Modeling these connections remains an open area to be worked out by neurobiological theories of addiction (Ray et al. 2012).
