Identifying genes that contribute to a low level of response to alcohol

October 14, 2004

Alcoholism is a complex, genetically influenced disorder. Multiple phenotypes - measurable and/or observable traits or behavior - contribute to the risk of developing alcoholism, particularly disinhibition, alcohol metabolizing patterns, and a low level of response (LR) to alcohol. A low LR to alcohol seems to be particularly relevant, with data indicating that LR relates to risk status, predicts future alcoholism, and has a heritability as high as 60 percent. A review in the October issue of Alcoholism: Clinical & Experimental Research examines previous research, seeking to identify those genes that may contribute to a low LR to alcohol.

"Prospective studies have shown that a low response to alcohol absolutely does increase your risk for future alcohol-related problems, at least in part by changing your expectations of what it is that you expect during drinking," said Marc A. Schuckit, director of the Alcohol Research Center, Veterans Affairs San Diego Healthcare System, professor of psychiatry at the University of California, San Diego, and first author of the study.

"However," Schuckit added, "the key is that people drink - especially early in their careers - for effect, which often means intoxication. An individual who experiences not much of an effect from alcohol will still feel effects like anybody else, but they'll just require more to do it, and this will probably impact their expectations of what alcohol is going to do for them."

"Different people have a different initial response to alcohol, also known as level of sensitivity," said David Goldman, chief of the Laboratory of Neurogenetics at the National Institute on Alcohol Abuse and Alcoholism. "Some people are a 'cheap date' or 'cheap drunk,' if you will, they're tipsy after only one drink versus others who can 'drink you under the table' and are still standing and not very affected even after several drinks."

Goldman noted that previous research has already taken step one, uncovering that a lower response to alcohol is predictive of future alcoholism. Step two, he said, was the discovery of the greater similarity in alcohol response between siblings or between parents and their offspring than you would expect from the random population, which directly implies there are genes that underlie that heritability. Step three, he added, is the current study that seeks to identify those genes.

Schuckit and his colleagues reviewed both animal and human English-language studies developed since January 1998, listed on Medline, and with appropriate keywords (n= 135). They then synthesized the studies' results, searching for potential patterns.

Reviewers identified several genes that may contribute to a low LR to alcohol, and thus, to an elevated risk for alcohol-use disorders. The genes of potential interest fall into several categories, including: second messenger systems, neurotransmitters or drug-related receptors, genes that affect alcohol metabolism, and genes that might relate to an overlap in the risk for alcoholism and some psychiatric conditions.

"There are genes in animals that have a huge impact on the intensity of response to alcohol," said Schuckit. "In most animal strains, but not all, if that animal has genes that contribute to a lower response to alcohol, they drink more in free-choice situations. Those contributing genes fall into a limited number of brain systems, which I have named. For readers who are interested in the genetics of alcoholism, we can say that the low response to alcohol is a major risk factor for alcoholism in the future, and it is genetically influenced. For researchers who are looking for genes, I can say 'let me save you some time,' because we have spent hundreds of hours reviewing the literature to try to find genes that might be contributing to the low response to alcohol in organisms, including humans."

"We are at the very beginning of 'gene finding' for alcohol response," said Goldman, "when it is important to understand the potential scope and breadth of the area rather than immediately homing in on just one narrow purpose, which might then preoccupy us for a long time while we miss the opportunity that's out there. Alcoholism is a complex puzzle of etiology; discovering the genes that contribute to level of response to alcohol would help to put together the whole puzzle, but right now we don't have enough pieces in our hands."

Schuckit added that he plans to test as many of the genes as he can. "It's very difficult work, expensive and time-consuming," he said. "We will be focusing on several chromosomal regions, several specific genes, and continue to collaborate with people doing animal research."
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Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, "The Search for Genes Contributing to the Low Level of Response to Alcohol: Patterns of Findings Across Studies," were Tom L. Smith and Jelger Kalmijn of the Department of Psychiatry at the University of California, San Diego and the Veterans Affairs San Diego Healthcare System. The study was funded by the National Institute on Alcohol Abuse and Alcoholism, the Veterans Affairs Research Service, and the State of California.

Alcoholism: Clinical & Experimental Research

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