Alcohol-dependence gene identified

Investigators at Washington University School of Medicine in St. Louis, Indiana University School of Medicine and other centers have identified a gene that appears to increase the risk of alcoholism.

The study, published in the January issue of the journal Alcoholism: Clinical and Experimental Research, is the first to demonstrate an association between this particular gene and alcohol dependence.

The gene is related to a receptor that allows for the movement of Gamma-amino butyric acid (GABA) between nerve cells. GABA is the major inhibitory chemical in the central nervous system.

“There were lines of evidence from other studies — animal studies, in vitro studies — that suggested GABA receptors are involved in the behavioral effects of alcohol,” says lead author Danielle M. Dick, Ph.D., research assistant professor of psychiatry at Washington University School of Medicine in St. Louis. “Because GABA receptor genes were likely candidates and previous studies had linked this area on chromosome 15 to alcoholism, we zeroed in on three GABA receptor genes but only found significant association with one of them.”

The study was conducted as part of the national Collaborative Study on the Genetics of Alcoholism (COGA), an ongoing project involving interviews and DNA samples from more than 10,000 individuals from inpatient and outpatient alcohol treatment centers and their families. Families in the COGA study usually have several members with alcohol dependence.

For this study, the investigators analyzed DNA from 262 families, a total of 2,282 individuals. They isolated three genes on chromosome 15 — GABRA5, GABRB3 and GABRG3 — that sit very close together on the chromosome. Then the investigators used markers called SNPs (single nucleotide polymorphisms) to study differences between the participants’ genes.

The markers demonstrated small genetic differences did appear to influence the risk of alcohol dependence, but only in one of the genes: GABRG3.

But it is not known how GABRG3 influences alcoholism risk. Dick says previous research has suggested chemicals that increase GABA receptor activity can accentuate the behavioral effects of alcohol, such as sedation, loss of anxiety and problems with motor coordination. Conversely, chemicals that decrease GABA receptor activity can have the opposite effect.

“This suggests that somehow GABA reception might be involved in these behavioral effects,” Dick says. “But we don’t know exactly how, so we can’t tell what the pathway might be that leads from GABA receptor genes to alcoholism.”

Finding that GABA is involved in alcohol abuse and dependence supports a current theory that predisposition to alcoholism might be inherited as part of a general state of brain overactivation. People at risk for alcoholism may inherit a variety of genes that contribute to this state. Perhaps alcohol normalizes that state of excitability, leading people with a hyperexcited nervous system to use alcohol more frequently in order to normalize brain circuits. That, in turn, would put them at greater risk for developing alcohol dependence.

Dick says it is important to point out that genetic make-up does not necessarily mean a person is doomed to become an alcoholic.

“One reason it is so difficult to find genes involved in psychiatric disorders is that there is an interplay between genetic and environmental factors,” she says. “A person can carry all kinds of genes that predispose them to alcohol dependence, but if they never take a drink, they won’t become an alcoholic.”

Dick DM, Edenberg HJ, Xuei X, Goate A, Kuperman S, Schuckit M, Crowe R, Smith TL, Porjexa B, Begleiter H, Foroud T. Association of GABRG3 with alcohol dependence. Alcoholism: Clinical & Experimental Research, vol. 28:1, pp. 2042-2047, January 2004.

This research was funded by the National Institute of Alcohol Abuse and Alcoholism of the National Institutes of Health.