FIGURE 4. How the Frequency of an Environmental Exposure in a Sample Influences the Ability to Detect Genetic Effects and G×E Interactions^a.

^a Panel A shows the influence of environmental exposure frequency on the ability to identify genetic effects, in two genotypes of equal prevalence. Genotype A shows no phenotypic response to the environmental exposure. Genotype B shows a response to the environmental exposure. What would happen if the association between genotype and phenotype were studied without knowledge of the environmental exposure and its frequency (shown from 10% to 90%)? A sample having many exposed subjects will report a genetic effect on the phenotype, whereas a sample having few exposed subjects will not, and if exposure is not ascertained, the source of nonreplication will remain a mystery. Panel B shows the influence of the rate of environmental exposure on statistical power to detect G×E interactions and main effects of genes. Each point is based on 10,000 simulations of samples of 1000 drawn from a population with equal distributions of two genotypes, with a continuous outcome generated as a moderately strong G×E (i.e., the difference in the environment-phenotype correlation between genetic strata =0.3), and no main effect. In samples with exposure frequency close to 0, there is no detectable interaction or main effect. For exposure frequency below 50%, there is greater power to detect a G×E interaction (blue line) than to detect a main effect of genes (red line). With rates of exposure exceeding 50%, the power of detecting a direct effect of genes (red line) increases above that of detecting an interaction, even though interaction is the data-generating mechanism. The probability of detecting a spurious main effect of genes (or environments) remains at the 2.5% chance level across the range of exposure frequency if the interaction term is retained in the equation.