This study is not without limitations. The screening and composition of the control group is crucial for studies of substance use and abuse [6, 31, 43]. Our controls indicated they had never used opiates not as prescribed, which could include individuals who had simply never used an opiate, along with individuals who had anywhere from minimal to extensive experience with opiates but had never deviated from their prescribed use. POU might be even more useful if we had additional data that allowed us to exclude individuals that have never used opioids. Using an unscreened control group can lead to considerable phenotypic heterogeneity across samples [7, 66]. Similarly, it is unclear what type of prescription painkillers the subjects included in our study may have used. Future studies with improved phenotyping around this topic and greater sample size could be even more productive. A second important limitation is our inability to evaluate whether the individuals included in our analyses suffered from mild versus severe pain. Although high genetic predisposition for chronic pain may itself be a risk factor for OUD, this concern
