The need for huge sample sizes is in part due to a combination of small effects and the large number of tests conducted in a GWAS (e.g., see (Burton, et al., 2009). The problem is compounded when studying developmental or environmental moderators of genetic effects (i.e., GxE or GxD designs). Gene x Environment-Wide Interaction Studies (GEWIS), for example, require at least as many tests as GWAS and much larger sample sizes to ensure adequate power for what is expected to be small GxE effects (e.g., sample sizes four times that for GWAS (Manolio, Bailey-Wilson, & Collins, 2006; Thomas, 2010a, 2010b)). There is presently little reason to believe that GEWIS would be more successful than GWAS have been (Caspi, Hariri, Holmes, Uher, & Moffitt, 2010). Add to this the difficulty of finding existing studies with large sample sizes that possess commensurate phenotypic and environmental measures such that meta-analysis or harmonization is difficult to impossible, and the success of exploratory GEWIS becomes less promising. Unless an a priori GxE hypothesis is extremely strong or the environmental effect is severe and/or uncommon (Caspi,
