The Role of the GABRA2 Polymorphism in Multiplex Alcohol Dependence Families with Minimal Comorbidity: Within-Family Association and Linkage Analyses * (Gamma-Aminobutyric Acid Gene‪)‬

THE NEUROTRANSMITTER [gamma]-aminobutyric acid (GABA) has been studied extensively because it is considered to be the major inhibitory neurotransmitter in the human central nervous system (Barnard et al., 1998). Genetic variation in GABA may be an important source of risk for developing alcohol dependence based on evidence from animal, human, and in vitro models. [GABA.sub.A] receptors in the human brain are sensitive to ethanol, as shown by altered expression of receptor subunit mRNAs in the cerebral cortex following chronic ethanol administration (Morrow et al., 1990). Positive emission tomographic studies of the metabolic response (2-deoxyglucose) to a benzodiazepine challenge in persons at risk for alcohol dependence have revealed reduced benzodiazepine inhibition (Volkow et al., 1997). Animal studies of [GABA.sub.A] transmission have been shown to influence alcohol preference (Nowak et al., 1998), tolerance (Hood and Buck, 2000), and withdrawal (Keir and Morrow, 1994). Specifically, [GABA.sub.A] agonists increase ethanol intake whereas antagonists cause a decrease (Boyle et al., 1993; Nowak et al., 1998; Tomkins and Fletcher, 1996), and a decreased sensitivity of the [GABA.sub.A] receptor in different areas of the murine brain is associated with both ethanol tolerance and dependence (Grobin et al., 1998). The [GABA.sub.A] receptor is composed of at least 19 known subunits, with the majority containing three types: (1) [alpha], (2) [beta], and (3) [gamma] (Barnard et al., 1998). Murine studies indicate that the gene encoding the [GABA.sub.A] [gamma]2 subunit, GABRG2, is involved with the severity of ethanol withdrawal and the motor and hypothermic effects of ethanol (Buck and Hood, 1998; Hood and Buck, 2000).