There are several possible explanations for the lack of replication. Addiction is a complex behavioral trait, and substantial heterogeneity exists between studies as there are a number of variables that may differ or may not have been controlled for across studies. Many studies have been underpowered, and different study methodologies (e.g. prospective vs. retrospective, population-based vs. clinical trial samples) may result in different sample populations. There is also a lack of consistency in phenotypes and outcome measures, such as definition of an appropriate control group (ever vs. former vs. never users). Inclusion of individuals of different ethnic backgrounds, while important for understanding predictors of diseases in these populations, may result in erroneous conclusions due to population stratification as allele frequencies and cultural acceptability of drug use may differ. GWA studies have indicated potential population stratification even within geographical regions previously considered to be genetically homogeneous. As such, the use of better selected controls and examination of ancestry informative markers may address these issues to an extent. The use of intermediate phenotypes, as discussed below, may also help improve reproducibility of
