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Genetic Clues to Alcoholism (or Why Mice Drink)

A study of the brain genetics of alcoholism in mice is unraveling the secrets of this disease in humans.

More money and research have probably been dedicated to studying the genetics of alcoholism than any other drug addiction. And so far the results have been disappointing. A recent large-scale study of mice, however, has provided researchers with some surprising new target genes that may be implicated in human alcoholism.

The study, which looked at most of the genes expressed in the brain, also demonstrates the speed and depth of studies of complex genetic diseases made possible by mouse models and increasingly cheaper DNA microarrays.

Researchers led by University of Texas at Austin neurobiologist Susan Bergeson analyzed gene expression data from mice bred for their alcohol preference – some were teetotalers, others prefered a 10-percent ethanol solution in their water bottles. The researchers examined gene expression across the entire brain of the mice. They found that 3,800 genes differ in expression levels between teetotaler and alcohol-loving mice. In particular, 75 of these genes seem to be associated with the mice’s penchant for more or less alcohol. And 36 of the genes are in stretches of the human genome that have been implicated in alcoholism.

The study combined research from scientists who are members of an NIH coalition called the Integrative Neuroscience Initiative on Alcoholism (INIA), and include researchers at the Oregon Health Sciences University, the University of Colorado, Scripps Research Institute, and the Indiana University School of Medicine.

Psychologists and geneticists hope that information about a patient’s genetic risk of alcoholism could provide better-tailored treatments. “If you knew why [your patient] was an alcoholic on the neurobiological level, that might help you,” says Jonathan Flint, a psychogeneticist at Oxford University’s Wellcome Trust Center for Human Genetics.

But so far scientists have been stymied by alcoholism’s complexity. “Alcoholism is at its root…almost a canonical example of a complex genetic disease,” says Robert Williams, geneticist and professor of anatomy and neurobiology at the University of Tennessee Health Science Center. Risk for alcoholism probably comes from several different genes that each play a small part, he says, and an individual alcoholic’s disease is probably caused by different combinations of these genes. This is likely the case because alcohol can interfere with so many chemical pathways in the brain. While many addictive drugs, such as cocaine, have a single target in the brain, ethanol is a “teeny little molecule that can wriggle its way into every network [and] has effects just about everywhere,” says Williams.

Given the genetic complexity of the disease, the search for alcoholism genes has been hindered by the tools geneticists have had at their disposal – only 10 or 15 years ago it was impossible to examine the expression of more than one gene at a time. In fact, Eric Nestler, chairman of psychiatry at the University of Texas Southwestern Medical Center in Dallas, who studies the genetics of addiction, says it’s been so difficult to find genes for alcoholism that “there’s been a bit of nihilism creeping into the field.”

But, Williams says, “We now have terrific tools,” such as increasingly cheaper, higher throughput DNA microarrays. “Looking for genes is getting faster.” The INIA study, he says, is an example of how quickly new models can be generated using these tools.

Because Bergeson’s group wasn’t looking at specific regions or for particular genes, the study had some unexpected results. One-quarter of the 3,800 candidate genes are of unknown function – the INIA group would have missed them with a narrower search.

We should “expect to be surprised” by the genes involved in complex diseases, says Nestler, because they “might not be obvious to us.” Indeed, of the 36 genes the INIA group poses as possible contributors to human alcoholism, says Williams, several are associated with non-neuronal brain cells, called glia, which researchers would not have guessed were involved with alcoholism.

Williams says broad approaches like Bergeson’s can illuminate surprising genes and help scientists avoid what he calls the “lamppost effect”: researchers studying addiction looking at the same group of genes and pathways – because that’s where the most illumination is.

Now the latest findings in mice need to be used to understand alcoholism in humans. The National Institute on Alcohol Abuse and Alcoholism, which funded the study, has a database of thousands of DNA samples from both alcoholics and their families. Bergeson says it would be relatively easy to bring this information together with her candidate genes from mice and look for commonalities.

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