If GxE interaction effects and similar intergenerational processes do indeed play an important role in the etiology of alcohol dependence, standard case control and prospective cohort studies using samples of unrelated people will have important limitations. These limitations become obvious when studying the model of GxE interaction effects shown in the figure. Under this model, given an adequately large sample size in a case control study, any gene that is a risk factor for alcohol dependence will also be identified as a genetic risk factor for major depression, even though the association with major depression arises solely via an environmental mechanism—the high-risk environmental exposures associated with the parent’s alcohol dependence that increase risk of depression in the parent’s offspring. In reality, however, such genes would influence the risk of depression only indirectly, through the environmental pathway from parental alcohol dependence to high-risk environmental exposures, which then interact with (other) genes that increase risk of depression (see Eaves and Sullivan 2001). Even controlling for alcohol dependence history in cases and control subjects will not remove this association, because it is the
