The relatively small sample size for the replication cohorts, especially when examining AA individuals, may have contributed to our limited evidence for replication. However, the neuroimaging extension provides evidence for an interesting, albeit preliminary, link between GWS loci and ventral striatum (VS) reactivity. For rs75168521, African American carriers of the C allele, which was associated with increased likelihood of ANYDEP in the COGA GWAS, had blunted response to positive versus negative feedback. Decreased reward sensitivity to rewarding, non-drug stimuli has been well documented within addiction, with evidence that this may arise following persistent drug exposure68. However, as the DNS sample is characterized by relatively low levels of substance use and related problems (other than alcohol31), the association between genotype and blunted VS response to reward may plausibly be viewed as a predisposing factor. One might speculate that individuals, particularly adolescents, with a blunted response to rewarding stimuli, in general, may require larger drug amounts or more potent drugs for reinforcement, and thus, be more susceptible to the development of severe addiction69. Such an interpretation is consistent with evidence that unaffected
