In direct contrast to the results for rs75168521, rs1890881 (chromosome 1) major T allele homozygotes, who were at increased risk for ANYDEP (driven by the association with alcohol dependence) in the COGA GWAS, had elevated reward-related VS response (identical to Lai et al.). While these findings may, on the surface, appear to be inconsistent with one another, literature suggests that both relatively reduced and heightened VS response to reward may be associated with substance involvement and dependence liability according to unique and shared mechanisms31. For example, evidence that reward-related VS activity is positively coupled with problematic drinking73 as well as behavioral and self-reported impulsivity74, converges with stage-based theories of addiction postulating that elevated impulsivity may lead to greater substance use exposure and experimentation that may lay the foundation for the development of problematic substance use. On the other hand, a parallel literature has also linked relative hypoactivity of the VS to drug-seeking behaviors, which has often been theorized to reflect compensation for blunted reactivity to reward71,75. Thus, it is plausible that blunted VS reward response associated with rs75168521 may confer
