Recent literature cautions the investigation and interpretation of significant differences in phenotypic variability across genotypes as well as observed GxE and GxG interaction effects.17,34–37 First, variance heterogeneity across genotypes can result from a mean-variance relationship induced by an inappropriate choice of measurement scale for the phenotype under investigation. Second, dependence between a causal locus and an exposure (G or E) can create synthetic interactions between the exposure and other tagged SNPs in incomplete LD with the causal locus.36,37 Consequently, we might observe phenotypic variance heterogeneity across genotypes of a tagged SNP.17 In these scenarios, however, because there is a true underlying genotype-phenotype relationship (main effect of G), it does not matter whether we detect this association through a location or a scale test, or both; the goal of our approach is to leverage complex genetic architecture to efficiently identify the associated G for follow-up investigation of causal interactors.