due to a variety of reasons including: (1) low effect sizes of variants where each significant variant detected by a genetic association study will have a small influence on an SUD (Marjoram, Zubair, & Nuzhdin, 2014); (2) insufficient power to detect significant associations resulting from low sample sizes particularly in single-site studies (Visscher, Brown, McCarthy, & Yang, 2012); (3) phenotypic heterogeneity due to variance in the measurement of SUDs across samples that may reflect different stages of SUD; (4) genetic heterogeneity characterized by an outcome arising from multiple sets of genes or genetic mechanisms that likely decrease the power to detect a significant genetic association specific to a substance; (5) racial/ethnic inconsistency between discovery and replication samples (i.e., participants of European ancestry in the discovery sample and African ancestry in the replication sample) that result in a failure to reproduce significant genetic association across samples as a result of differences in ancestry-related local haplotype structures at loci associated with SUD (Enoch, 2013; Melroy-Greif, et al., 2017; Polimanti, Yang, Zhao, & Gelernter, 2015; Verweij, et al., 2012) and (6) phenotypic comorbidity where the SUD diagnosis, itself, may have multiple subtypes (i.e., single-drug versus poly-drug dependence, rate of time from initiation to
