Accordingly, this receptor likely is involved in dependence on these drugs as well (Orser 2006). The GABAA receptor is composed of five subunits that are encoded by numerous genes, most of which are located in clusters. Thus, chromosome 4 contains a cluster comprising the genes GABRA2, GABRA4, GABRB1, and GABRG1; chromosome 5 contains GABRA1, GABRA6, GABRB2, and GABRG2; and chromosome 15 contains GABRA5, GABRB3, and GABRG3 (see http:// entrez?db=gene). Interest in the GABAA receptor genes on chromosome 4 grew when this region consistently was identified in genome-wide scans looking for linkage with alcohol dependence (Long et al. 1998; Williams et al. 1999). Subsequently, COGA investigators systematically evaluated short DNA segments of known location (i.e., genetic markers) that were situated in the GABAA receptor gene cluster on chromosome 4. These studies found that a significant association existed between multiple SNPs in the GABRA2 gene and alcohol dependence (Edenberg et al. 2004). This association has been replicated in multiple independent samples (Covault et al. 2004; Fehr et al. 2006; Lappalainen et al. 2005; Soyka 2007). In addition, the same SNPs in the GABRA2 gene have been shown to be associated with drug dependence in both adults and adolescents (Dick et 4 Rapid acetaldehyde production can lead to acetaldehyde accumulation in the body, which results in highly unpleasant effects, such as nausea, flushing, and rapid heartbeat, that may deter people from drinking more alcohol. 5 For example, the medication disulfiram, which inhibits another enzyme involved in alcohol metabolism called aldehyde dehydrogenase 2 (ALDH2) and is used for treatment of alcoholism, has demonstrated a treatment effect in cocaine dependence (Luo et al. 2007). Alcohol Research & Health 114
Genetics of AOD Dependence al. 2006a), as well as with the use of multiple drugs in another independent sample (Drgon et al. 2006). Variations in the GABRA2 gene are associated not only with AOD dependence but also with certain electrophysiological characteristics (i.e., endophenotypes) in the COGA sample (Edenberg et al. 2004). As reviewed above, these electrophysiological characteristics are not unique to alcohol dependence but also are found in individuals with other forms of externalizing psychopathology. This association supports the hypothesis that the GABRA2 gene generally is involved in AOD use and/or externalizing problems. Interestingly, subsequent analyses investigating the role of GABRA2 in drug dependence (Agrawal et al. 2006) found that the association with GABRA2 was strongest in people with co-morbid AOD dependence, with no evidence of association in people who were only alcohol dependent. This observation supports the assertion that co-morbid AOD dependence may represent a more severe, genetically influenced form of the disorder.