A number of challenges underlie G x E studies and their application remains controversial to some. One of the main issues is that just as the genetic factors underlying drug addiction are not well known, the set of relevant environmental factors are also not clearly understood. As such, the discovery of G x E interactions depends on having appropriate subgroups (particularly those with a sound theoretical or biological basis) in the analyses where the genetic factors are having an effect. Inappropriate subgrouping may lead to erroneous conclusion of a lack of genetic, environmental or G x E effect, and failure to replicate a G x E results may be due to the effect acting upon further subgroups compared to those examined in the original study. However, particular care must be taken in selecting subgroups as unguided exploration through the endless permutations of possible subpopulations increases the risk of Type I errors, making the criteria for replication more stringent. Well-validated and consistent measures of environmental factors are needed, as some G x E interactions has been shown to be artifacts caused
