Gene-discovery studies of human alcohol dependence have evolved considerably from the basic test for differences in the frequency of specific alleles between diagnosed cases and screened controls. Such studies now often include a range of categorical and quantitative phenotypes, reflecting our growing understanding that multiple underlying risk pathways influence alcohol dependence. Some pathways (such as physiological differences in how alcohol affects an individual) are likely specific for alcohol dependence. For example, initial sensitivity to alcohol is strongly and inversely related to risk for alcohol dependence64. However, the only variants that affect sensitivity to alcohol and have known functional impact on alcohol dependence risk are in genes encoding the alcohol dehydrogenase (ADH) 1B and 1C65–68 and aldehyde dehydrogenase 2 (refs. 69,70) enzymes, and they confer substantially reduced, rather than increased, risk for alcohol dependence by causing aversive reactions to ethanol.
