The case-only design is appealing for a GEWIS because of its greater power than the case-control design and because most GWA SNPs are unlikely to be correlated with environmental factors in the source population. Nevertheless, some false positives due to G-E association may occur, and even if only a small proportion of all SNPs were associated, they could represent a high proportion of all reported G×E interactions. Since any scan for interactions is likely to have been accompanied by a main effects scan, controls are probably available anyway, so it would be wasteful not to use them. (The exception would be if public controls with no environmental data, or non-comparable data, were used for the main effects scan, combining case-only information on G×E interactions with case-control information on genetic main effects98.) Two basic approaches have been suggested for taking advantage of controls to protect against false positives while exploiting the power advantage of the case-control design. Murcray et al.99 introduced a two-step analysis of a single-stage GWA study (FIG 1), in which G-E association is first tested in the combined
