There are several additional explanations for between-genotype variance heterogeneity, such as variance misclassification that can occur when the index variant is located within a haplotype containing rare functional variants that convey strong marginal effects . Hence, although variance heterogeneity tests represent a useful data-reduction step, before conclusions are drawn about the presence or absence of G×E interactions, index variants should be validated by testing their interactions with explicit environmental exposures, as we did here with smoking and physical activity. However, genome-wide G×E interactions datasets are not comprised of functionally validated G×E interactions, as no such resource is currently available for human complex traits. This limitation inhibits the extent to which causal effects can be attributed to the top-ranking loci and their interactions with smoking or physical activity.