Taken together, the preceding genetic variants affect the pharmacokinetics of alcohol and further underscore the importance that genetic influences on the subjective effects of alcohol have on risk for AUD. Allelic variation that either results in faster initial accumulation of acetaldehyde (ADH-related genes) or slower breakdown of acetaldehyde (ALDH-related genes) largely determine whether an individual will experience an acutely aversive reaction to alcohol and, in turn, significantly affects the risk for the development of AUD. As such, acetaldehyde accumulation syndrome, including its behavioral effects, is a prototypical intermediate phenotype, intervening between genetic variation and disease liability. Although substantially more remains to be understood about the genes responsible for alcohol’s metabolism, these findings are highly illustrative of an intermediate phenotype approach, and may also provide a model system for potential interventions.
