(CHRNA5)-rs16969968 with cigarette smoking, two of the most robust and replicable genetic effects in the substance use literature, have been found to differ as a function of trauma exposure13,23,24. However, critiques of early GxE studies pointed to the likelihood of false positive findings given the focus on candidate genes and small sample sizes typical of many well-characterized (i.e., deeply phenotyped) genetic studies, as well as other important methodological considerations25. For example, Keller26 illustrates the importance of accounting for confounding effects of other two-way interaction terms (e.g., G × covariate, E × covariate), which can complicate the interpretation of regression-based GxE analyses.
