Alcohol Metabolism and Alcoholism

The first gene strongly associated with alcoholism was DRD2. It was a false association because the alcoholics were mostly Mexican Americans and the controls mostly European Americans. Our studies showed that the variant that “caused” alcoholism has its highest global frequency in Native Americans and a relatively low frequency in Europeans. That work started a quest to study more broadly the population genetics of susceptibility to alcoholism. Some of the strongest associations are with genetic variants that alter ethanol metabolism with the primary effect of providing resistance to alcoholism. The frequencies of the variants have different global patterns. Several of the individual genes in the alcohol dehydrogenase family of genes are involved and the most studied variant is widespread with higher frequencies in East Asia and Southwest Asia. The aldehyde dehydrogenase 2 locus has a particularly sharply defined variant pattern with high frequency in Southern coastal China, lower frequency most everywhere else in East Asia, and absent elsewhere. Genomic analyses argue that positive selection is responsible for the high frequencies of these variants but fail to illuminate the selective force. Details of the population studies of these and other genes will be presented.