Many previous studies indicating a role for GABA system genetic variation in alcohol dependence were conducted using as cases individuals drawn from treatment programs for alcohol dependence, or other clinical settings (eg. Lappalainen et al., 2005). Some, such as those involving the samples from the Collaborative Studies on Genetics of Alcoholism (COGA) (Rice et al., 2003), included participants belonging to families of probands with multiple alcohol-dependent first-degree relatives (Agrawal et al., 2006; Edenberg et al., 2004). Alcohol-dependent cases with severe phenotypes and family history of alcohol dependence may have an elevated genetic loading for the disorder, making the detection of genetic effects more likely. In one clinically-derived sample, associations between markers in GABRA2 and alcohol dependence increased when analyses were restricted to include as cases only individuals with indicators of severe or persistent alcohol dependence, or a family history of alcohol dependence (Fehr et al., 2006). Other studies suggest that GABRA2-related alcohol dependence vulnerability is limited to individuals with comorbid dependence on illicit drugs (Agrawal et al., 2006), or that GABRA2 markers are related to polysubstance abuse, but not alcohol
