Progress towards finding genes for alcoholism in mice

Alcoholism is a debilitating disease that affects one in 13 adults in the US. It is a complex genetic disorder, influenced by multiple genes of small effect. The purpose of this review is to discuss how studies of mice have been used to search for the genes that underlie alcoholism. Features of alcoholism, such as alcohol dependence, tolerance, and impaired control over alcohol drinking have been successfully modeled in mice. Comparisons across strains that differ in genetic makeup have shown that these traits have a genetic component. Standard inbred strains are particularly useful for this purpose, because genetic uniformity within the strains increases power to detect differences among strains. Three approaches have been used to find specific genes that underlie an alcohol trait: genetic engineering, gene expression profiling, and quantitative trait locus (QTL) mapping. We discuss the advantages and disadvantages of each, but emphasize QTL. QTL mapping is designed to detect multiple genes of small effect, has the potential to find new genes related to alcoholism, and is useful for inferring a cause and effect relationship between a gene and a trait. The initial result of a QTL analysis identifies a region of a chromosome that harbors at least one gene affecting the trait. The long-term goal is to narrow the size of the chromosomal region until it contains a small number of genes that can be directly tested for their role in the disorder. The furthest progress has been made for alcohol withdrawal where a region harboring only 18 genes or gene-related sequences was identified. A strong candidate gene, Mpdz, was subsequently identified in this region. Mpdz codes for a protein that functions to couple ligands to their receptors. Current work is investigating the possible function of Mpdz in alcohol withdrawal. Ultimately this research might lead to the development of new diagnostic tools and pharmacotherapies to treat alcoholism.