Consistent with functional studies of the GABAA receptor, COGA linkage studies had identified a large DNA region located on chromosome 4, which contains the GABRA2, GABRA4, GABRB1, and GABRG1 genes, as being related to the risk of alcoholism (Porjesz et al. 2002). For these analyses, COGA investigators used a strategy that tests for endophenotypes—basic biologic features of complex disorders—rather than the usual phenotype (e.g., alcoholism). In this case, the endophenotype was an electrophysiological measure of brain function known as the P300 component of an event-related potential (ERP). ERPs are specific brain waves that occur in response to a sudden stimulus (e.g., a sudden sound or light). Within these brain waves, a particular spike typically occurs about 300 milliseconds after the stimulus; this is the P300 wave. A reduced size (i.e., reduced amplitude) or delayed appearance of the P300 brain wave has been found both in alcohol-dependent people and in people at increased genetic risk of becoming alcohol dependent (Porjesz et al. 2003). Hence, both linkage results and molecular biological studies have suggested that variation in the GABAA receptor might be involved in alcohol dependence.
