Pharmacogenetics of responses to alcohol and genes that influence alcohol drinking

Objective: There is now compelling evidence for genetic influence on susceptibility to alcoholism. This article presents results from studies qualifying alcoholism as a pharmacogenetic disorder of the brain. Method: Studies from the author's research group and other investigators, of human subjects and experimental animal models, are reviewed. Included are experiments on the pharmacogenetics (elimination and metabolism) and pharmacodynamics (initial response, tolerance and dependence) of ethanol. Results: Studies in humans have reliably shown that the genes for the principal enzymes of alcohol metabolism influence drinking behavior and alcoholism risk. Notably, the functional genetic variants of alcohol dehydrogenase that exhibit high alcohol oxidizing activity, and the generic variant of aldehyde dehydrogenase that exhibits low acetaldehyde oxidizing activity, protect against heavy drinking and alcoholism. Extensive studies of inbred and selectively bred experimental rodent models with alcohol drinking preference, tolerance development and alcohol withdrawal susceptibility have shown strong genetic influence on these responses to ethanol. Neuroanatomical, neurochemical and genetic studies have shown the involvement of serotonin, dopamine, glutamate, gamma-aminobutyric acid and opioid pathways in these actions of ethanol. Genetic studies, including association and genome-wide survey studies in both humans and rodents, implicate serotonin Ib receptor, dopamine D2 receptor, tryptophan hydroxylase and neuropeptide Y as candidate targets of genetic susceptibility in these pharmacodynamic actions of ethanol. Conclusions: There are genetic predisposing factors for alcoholism. Nonspecific Susceptibility factors include personality traits characterized by behavioral inhibition (e.g., novelty-seeking and impulsivity). These genetically influenced traits interact with other, also genetically influenced, traits involved in the metabolism and pharmacodynamic effects of alcohol, and this interaction forms the basis for nominating alcoholism as a pharmacogenetic disease. Clearly, there are also many environmental factors that influence drinking behavior. Individuals have different sets of susceptibility genes and experience different kinds of environmental provocation. These factors underlie the heterogeneity and complexity of the clinical phenotype of alcoholism.