Prior GWAS have utilized varied addiction phenotypes and biomarkers as well as study designs. A major distinction among the case-control studies involves the assessment of substance use and misuse for controls. Some studies have used population-based, unassessed controls when study controls were not available, for example [119], or when intending to increase sample size and statistical power with minimal offset from misclassification due to the relatively low prevalence of addiction, particularly for illicit drugs in healthy cohorts [112]. Other studies have focused on assessed controls with prior exposure or history of misuse but without symptoms of addiction, for example [110], aimed at detecting genetic variants associated with progression from misuse to later stages of addiction. Relatedly, studies with assessed controls have either adjusted for co-morbid exposure and/or addiction to other substances as covariates, under the premise of identifying genetic variants associated with specific substances, for example [105, 109]. Other studies have not adjusted for other substance co-morbidities [110], which may enhance detection of generalizable genetic variant associations. To our knowledge, there has been no formal testing to outline the best
