Genome-wide linkage studies, which examine whether large genetic regions distributed across the entire genome are cotransmitted along with a disease within families, were the first genetic studies to query the entire genome with hundreds or thousands of genetic markers. These studies had two main characteristics: they were family based, and the marker coverage across the genome was modest. Although these linkage studies implicated multiple regions of the genome as being involved in the development of alcoholism, the most consistent findings have pointed to two regions on chromosome 4, with peaks at chromosome locations 4p13–4p12 and on 4q21–4q23.2 The 4q21–4q23 region covers the cluster of alcohol dehydrogenase genes that includes, among others, ADH1B, supporting the candidate gene findings that alcohol-metabolizing genes are associated with alcohol dependence. The chromosome 4p13 region also contains a cluster of genes encoding the α-subunit of the receptor for the inhibitory neurotransmitter γ-aminobutyric acid (GABA), suggesting that polymorphisms in this receptor also may be involved in the development of alcohol dependence. This cluster of GABA receptor genes is of particular interest because of their putative biological relevance to alcohol-related behaviors, as discussed in the following section.
