Alcohol research is an area where one might imagine gene–environment interaction effects to be particularly important in etiological models because, by definition, exposure to alcohol is a necessary condition for the eventual development of alcohol-related problems. For example, one of the most widely replicated genetic associations with alcohol dependence is the protective role of a genetic variant responsible for the enzyme aldehyde dehydrogenase (i.e., ALDH2).1 The enzyme produced by a genetic variant in ALDH2 is comparatively inactive, interfering with the metabolism of alcohol, which leads to facial flushing and other aversive physiological symptoms when alcohol is consumed (Shen et al. 1997). Accordingly, the association between this gene and risk for alcohol dependence necessarily operates through alcohol exposure. Environments that modify the extent of exposure to alcohol therefore would be predicted to moderate the degree to which genetic variability is important. In the extreme, this becomes obvious. If there is no alcohol in the environment, then genetic risk factors for AUDs cannot, by definition, express themselves.
