A number of limitations of GxE research using candidate genes (cGxE) have been identified (Duncan and Keller 2011). Notably, publication bias against null GxE results inflates the number of published false positives—a problem that is amplified by the increased power requirements of interaction models relative to main effects. In addition, poorly-understood genotype-to-phenotype pathways render theorized mechanisms of GxE tenuous (Duncan and Keller 2011). Because the sample used in the current study is large and there is substantial variation on the candidate genotype and the outcome of interest (i.e. alcohol dependence) in both genders, concerns about adequate power are minimized. Moreover, the pathways through which GABRA2 may affect substance abuse and dependence (i.e. impulsivity and stress response) have been theorized and tested (e.g. Dick et al. 2013; Edenberg et al. 2004; Villafuerte et al. 2012, 2013), and these are consistent with the GxE effect presented in this study and GxE effects in previous research (e.g. Dick et al. 2001, 2009, 2013; Nilsson et al. 2005; Pescosolido et al. 2008; Rose et al. 2001). However, because cGxE research poses methodological challenges that
