Figures 1, 2, and 3 illustrate three basic forms of gene-environment dependence. Association of a gene with an environmental risk factor is often taken to imply mediation of the genetic effect by the risk factor. That is, at least part of the effect of the gene on the outcome is via its effect on the environmental factor. For example, a variant at the CYP3A locus might directly affect levels of the hormone estradiol, which influences age at menarche, which then directly affects breast cancer risk (Figure 1).