A conventional two-step analysis of G×G interactions in a single-stage GWA study restricts the search for interactions to gene pairs for which one or both members shows a marginal association. It can be more powerful than an exhaustive scan for all possible pair-wise interactions, but risks missing those with no or weak marginal effects8,95-97. In addition, scanning for higher-order (G×G×G…) interactions is computationally infeasible without filtering based on main effects and/or lower-order interactions. While this filtering approach could also be applied to G×E interactions, it does not exploit the ability of the following two-step approaches to use different designs.
