Genetic markers of alcohol abuse

In this paper, we review the current status of genetic markers for the development of alcohol abuse. Family, twin, half-sibling and adoption studies of alcoholic subjects suggest that the heritability of liability to alcoholism is at least 50%. These findings have fuelled intensive investigation in the fields of neurology, biochemistry, genetics and molecular biology aimed at the identification of markers for the risk of alcoholism. The most promising of these are discussed in detail. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) polymorphisms, specifically the ADH3*1, ADH2*2, and ALDH2*2 genotypes appear to confer a protective effect against alcoholism, most notably in Oriental subjects. Caucasian alcohol abusers and their first-degree relatives exhibit depressed platelet monoamine oxidase activity, the degree of which is greater in Type II than Type I alcoholics. Electrophysiological characteristics of alcoholics and those at risk for developing alcoholism have also been identified, including the reduced amplitude of the event-related brain potential and, after ethanol ingestion, characteristic EEG alpha-wave activity. Lower platelet adenylate cyclase activity is seen in alcoholics compared to controls, presumably as a result of over-expression of an inhibitory G-protein. Markers related to other signal transduction pathways of the central nervous system including the serotoninergic, muscarinic and dopaminergic systems are also discussed. In this group of markers, the putative association between the inheritance of the AI allele of the D2 dopamine receptor and the susceptibility to alcoholism provides the most dramatic illustration of the challenges presently existing in this field of scientific investigation. Current limitations in the definition, diagnosis and classification of alcoholism, the confounding influences of race and gender on association studies, as well as the statistical approach of linkage studies are discussed as they relate to the endeavor to uncover valid genetic markers for the risk of alcoholism.