Although only one of the Group 10 contributions tested for population stratification [Arya et al., 2009], it should be considered in all studies of G×E interaction. Population stratification can occur when systematic differences in allele frequencies exist between subgroups of a population, often corresponding to distinct genetic ancestry. This is an issue for GWAS because it can result in erroneous associations with the outcome. For analyses including G×E interactions, population stratification is an issue if population membership is associated with the outcome, the genetic effect, and the environmental exposure. One way to determine this is first to test for population stratification, i.e., by employing principal-components analyses using the software EIGENSTRAT [Patterson et al., 2006; Price et al., 2006]. If distinct populations are found, then population membership can be tested for association with the environmental variable as well as with the outcome. A priori criteria for a measure of association should be determined by the investigator. In this scenario, it is assumed that the association with the genetic effect is established through the principal-components analysis. If population membership is also found to be associated with the environmental exposure and the outcome, then the final analyses should adjust for population stratification.
