likely that at least some of the poor track record of replicating claims of G×E interactions is due to underpowered studies in the initial discovery or replication attempts19-21. This has led some to suggest that the search for interactions is not worthwhile, as genes involved in interactions are more likely to be detected through their marginal effects22. Nevertheless, a range of interaction effect sizes can be detected in a GWA study by either a test of interaction or a genetic effect in an environmental subgroup even when the marginal effects are not detectable (Suppl. Fig. 1c). Despite claims that interaction in the absence of main effects is a “ubiquitous” phenomenon in nature23,24, most examples are found at the molecular or cellular level and there are few convincing examples in human epidemiology. Nevertheless, there are examples of genetic effects that are apparent only groups with the relevant environmental exposure or of environmental factors that affect only those with the susceptible genotype (Box 1).
