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Researchers studying familial alcoholism have identified what they believe to be the first gene that increases risk of alcohol dependence by modifying a receptor that regulates actions of the neurotransmitter gamma-amino butyric acid (GABA).

GABA is the major inhibitory neurotransmitter in the human nervous system, but only one version of the gene, GABRG3 on chromosome 15, was shared by members of alcoholic families, according to scientists at five research facilities participating in a 15-year federally-funded search for a better understanding of the disease. Their findings appeared in the January issue of the journal Alcoholism: Clinical and Experimental Research (2004;28(1):4–7).

The study is one of the first to demonstrate a consistent association between alcohol dependence and GABRG3, said lead author Danielle M. Dick, PhD, Research Assistant Professor of Psychiatry at Washington University School of Medicine in St. Louis, MO.

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“Because GABA receptor genes were likely candidates and because earlier studies had linked this area on chromosome 15 to alcoholism in both clinical and animal studies, we zeroed in on three GABA receptor genes but found significant association with only one of them,” she said.

(GABA receptors comprise different homologous subunits that are functionally and structurally diverse. GABRB3, GABRG3, and GABRA5 – the focus for this study – form a cluster on chromosome 15.)

The research 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 people, selected from inpatient and outpatient alcohol treatment centers, and their families. COGA is a $65-million study funded by National Institute on Alcohol Abuse and Alcoholism (NIAAA).

The researchers identified regions of different chromosomes that are shared by members of families with a history of alcoholism, but the exact mechanisms by which genes influence alcoholic dependence remains a mystery, said Dr. Dick.

“We're starting to chip away at the edge of the iceberg … but we don't have a clear picture yet,” she said, explaining that both animal and in vitro studies have suggested GABA receptors are involved in the behavioral effects of alcohol.

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Research has shown that familial transmission of alcoholism risk is at least in part genetic and not just the result of environmental factors. For example, identical twins have the same genes and are about twice as likely as fraternal twins, who share on average 50 percent of their genes, to being vulnerable to alcoholism (Psycholog Med 1997;27:1381–1396). Other studies have reported that 50 to 60 percent of the risk for alcoholism is genetically determined, for both men and women (Am J Psychiatry 1999;156:34–40).

In this new study, Dr. Dick and her colleagues collected DNA samples from 2,282 people from 282 families heavily affected by alcoholism. Using single nucleotide polymorphisms as markers, the research team isolated three genes – GABRA5, GABRB3, and GABRG3 – located closely together on chromosome 15. They then compared differences between the participants' genetic makeup and their alcoholic status.

Prior research had suggested that agents that increase GABA receptor activity heighten the effects of alcohol while those that decrease GABA activity often have the opposite effect, said Dr. Dick.

“For example, chemicals that increase the activity of GABA receptors tend to accentuate the behavioral effects of alcohol, such as lack of motor coordination, sedation, and withdrawal signs, while chemicals that block GABA receptors lessen these effects.”

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The scientists have also found evidence of GABA regulation in genes on chromosome 4 in linkage studies.

“There are many genes in each region, so this takes time,” said Dr. Dick. “Our chromosome 4-receptor study is still in press. But it looks like this research method is robust. We just don't know the exact pathways and alterations in GABA regulation yet.”

Kirk Wilhelmsen, MD, PhD, Associate Professor of Genetics and Neurology at the Carolina Center for Genome Sciences at the University of North Carolina at Chapel Hill, said that additional genetic findings will be coming soon from other research groups, including his own.

“I think this is clearly an early success and we are expecting more findings in the future involving other genes. The real issue is to figure out the phenotype for alcohol dependency in the general population,” he said. “There is overwhelming evidence that chromosome 4 is involved. Our own studies show linkage among a number of other genes and chromosomes.”

Several papers describing Dr. Wilhelmsen's findings are being reviewed for publication and point to other genetic differences in GABA receptor activity in alcoholism.





“It's a very complicated area, and it's difficult … but we're starting to get a better picture. It's pretty critical that we find out which other genes are involved. I hope this is just a beginning.”

Dr. Dick agrees: “It is important to emphasize that there is no single alcoholism gene. Our findings and those of others suggest that GABA reception is somehow involved in the behavioral effects of alcohol, but we do not know exactly how, so we cannot tell the exact pathway or pathways that might lead from GABA receptor genes to alcoholism.”

Nonetheless, discovering that GABA is involved supports a current theory that predisposition to alcoholism might be inherited as part of a general state of brain over-activation or stimulation.

“Alcohol might normalize this state of excitability, leading people with a hyper-excited nervous system to drink more often and in greater quantities than other people, to normalize brain circuits,” she explained.

Dr. Dick emphasized that genes alone do not necessarily mean a person is doomed to become an alcoholic. “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,” she said.

She also cautions that the new findings only suggest a “potential” relationship between the GABA gene on chromosome 15 and the risk for alcoholism.

“Until this relationship is more clearly understood through studies of brain cells, for example, it will not be possible to directly apply this new knowledge toward education, prevention, intervention, or treatment,” she said. “The next step is to try to identify the specific genetic variation.”

“We need to find out the other ways that GABA is involved, and we are using this study to identify other genes and the subtle variations involved in order to help eventually develop a genetic risk profile.”

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✓ Researchers studying familial alcoholism have identified a version of the gene that they believe increases risk of alcohol dependence by modifying a receptor that regulates actions of the neurotransmitter gamma-amino butyric acid.

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For years, studies in rats have indicated genetic risks for alcoholism, prompting interest in human clinical trials. Other clinical studies have implicated genetic risks, but few involve actual family members.

“There are a lot of reports that one [genetic] variant is more prevalent in alcohol dependency, but almost all involved unrelated individuals. One unique aspect of COGA is we're investigating entire families,” said Danielle M. Dick, PhD, Research Assistant Professor of Psychiatry at Washington University School of Medicine in St. Louis.

Using variations in the DNA sequence as markers, and their association with alcoholic susceptibility, other COGA researchers have identified certain “hotspots” for alcoholism risk on five chromosomes – 1, 2, 4, 7, and 11 – including a “protective” area on chromosome 4 near the location of genes for alcohol dehydrogenase (Alcohol Res Health 2002; 25(3):214–220).

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• Dick DM, Edenberg JH, Xuei X, Association of GABRG3 with alcohol dependence. Alcohol Clin Exp Res 2004;28(1):4–9.
    ©2004 American Academy of Neurology