Molecular genetic approaches to the study of individual risk in alcoholism.

Genetic studies of alcoholics, their families and controls have given credence to the idea that genetic influences in alcoholism exist, and set the stage for efforts to identify alcoholism-susceptibility genes (Devor and Cloninger, 1989). My purpose is not to review the genetics of alcoholism, but rather to review the genetic approaches that have been successful in identifying the genes responsible for genetic conditions such as muscular dystrophy and cystic fibrosis. In these disorders our current knowledge of the basic biochemical defect was derived directly from the cloning of the gene that is defective in the disorder. The cloned gene provides DNA probes for carrier identification and prenatal diagnosis, while knowledge of the basic defect allows new and direct investigation of potential therapeutic strategies. The genetic approach is much less definitive when it comes to the study of polygenic or multifactorial disorders such as schizophrenia or Alzheimer's disease. In the case of alcoholism the problem is exacerbated not only by environmental factors but also by phenotypic and genetic heterogeneity. The lack of a clear inheritance pattern means that plausible modes of inheritance must be invoked and tested on families with multiple affected members. Direct segregation analysis may not be possible and the less informative analysis of sib-pairs may be the method of choice. Ultimately, however, it should be possible to identify and clone those genes that play a major role in determining susceptibility to alcoholism. Once cloned, the protein products can be identified, and study of their function should lead to new understanding of the complex biological processes involved in this disorder.