Overall, our results further support the role of DRD2 in negative reward learning, and suggest a central role for Neuroticism as an endophenotype linking PENK polymorphism to cannabis-dependence vulnerability synergistically amplifying the apparent genetic risk. Future studies are needed to correlate neurobiological outcomes with behaviors in animal models and other human populations. Nonetheless, this study suggests that subthreshold mood and anxiety symptoms that do not meet criteria for a DSM-IV disorder may have serious clinical implications. Prevention and early intervention approaches that focus on coping strategies among young individuals genetically prone to Neuroticism may prove to be helpful, and should be specifically examined in such populations.
