Sample size requirements for G×E studies can be enormous. A useful rule-of-thumb is that detection of an interaction requires at least four times the sample size than for detecting a main effect of comparable magnitude16. Sample sizes in the thousands of cases are typically needed for G×E analyses in candidate gene studies (Suppl. Fig. 1a) and tens of thousands in GWA studies because of the more stringent significance levels required (Suppl. Fig. 1b). In addition to study design, the key determinants of power or sample size requirements are the prevalence of exposure (or its distribution if continuous), the allele frequency, mode of inheritance, Interaction Odds Ratio ORG×E (and to a lesser extent the ORs for the main effects), significance level, and desired power. Several programs for sample size and power calculations are freely available, notably Quanto17 and POWER18. It is 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
