Systems genetics of alcoholism.

Alcoholism is a common disease resulting from the complex interaction of genetic, social, and environmental factors. Interest in the high heritability of alcoholism has resulted in many studies of how single genes, as well as an individual's entire genetic content (i.e., genome) and the proteins expressed by the genome, influence alcoholism risk. The use of large-scale methods to identify and characterize genetic material (i.e., high-throughput technologies) for data gathering and analysis recently has made it possible to investigate the complexity of the genetic architecture of susceptibility to common diseases such as alcoholism on a systems level. Systems genetics is the study of all genetic variations, their interactions with each other (i.e., epistasis), their interactions with the environment (i.e., plastic reaction norms), their relationship with interindividual variation in traits that are influenced by many genes and contribute to disease susceptibility (i.e., intermediate quantitative traits or endophenotypes) defined at different levels of hierarchical biochemical and physiological systems, and their relationship with health and disease. (An endophenotype is a genetically determined trait [i.e., phenotype] that is not immediately visible but may contribute to the susceptibility to develop a particular behavior or syndrome. See the glossary, p. 84, for descriptions of other technical terms used in this article.) The goal of systems genetics is to provide an understanding of the complex relationship between the genome and disease by investigating intermediate biological processes. After investigating main effects, the first step in a systems genetics approach, as described here, is to search for gene-gene (i.e., epistatic) reactions.