Gene Discoveries Poised to Transform Alcoholism Care

Researchers are also identifying interactions between candidate alcoholism genes and other factors. For example, studies of Plains Indian men and women and of Finnish men showed that GABRA2 was a risk gene for alcoholism when coupled with anxiety. A short form of the SLC6A4 gene was first linked with depression in the context of stressful life experiences. Now this form has been found in depressed alcoholics as well. A particular variant of the OPRM1 gene has not only been linked with alcoholism and opioid addiction, but with neuroendocrine responses to stress.

“Our knowledge in these areas has increased dramatically during the past 10 years,” observed Marc Schuckit, M.D., a distinguished professor of psychiatry at the University of California, San Diego, and a pioneer in alcoholism-gene research.

But more research in this arena is needed, Henry Kranzler, M.D., a professor of psychiatry at the University of Connecticut and an alcoholism-gene scientist, stressed, “since alcoholism is a complex disorder in the sense that there are both robust genetic and environmental effects.” Also, the search for alcoholism genes per se is far from over, he emphasized. “If you add up all the alcoholism genes that we have identified, they are still not going to account for what we have found in twin and adoption studies—that is, that 50 to 60 percent of the risk for alcoholism is inherited.”

David Mrazek, M.D., chair of psychiatry at the Mayo Clinic, concurred:“ I think the reason why I can't just give you a list of 10 alcoholism genes and say we're done is because different genes interact in different people to lead to this very complex addictive behavior. If you are somebody from Japan, you might have one set of genes that causes you to have an addiction problem. If you are somebody from Italy, you might have a different set of genes.”

Nonetheless, the alcoholism-gene discoveries that have been published are influencing the public's view of alcoholism. For example, when he started his alcoholismgene research three decades ago, Schuckit said, “people were still asking whether alcoholism might be genetically influenced.” Today, he said, they realize that it is both environmental and genetic.

Moreover, the discoveries to date are providing the public with guidelines on alcoholism prevention. For instance, Mrazek pointed out, “Schuckit has shown quite clearly in his studies that if you are the son of an alcoholic, and if you have the ability in your teenage years of being able to drink more than average, and you enjoy it, that combination is really worrying. You probably have some genes that put you at risk of developing alcohol dependence, and you don't have genes that help protect you against it. These are young people you should particularly work with to understand the danger for them personally.”

And while none of the alcoholism-gene findings are being used clinically at this time, some may become clinically applicable in the near future.

Take the prospect of using genes to identify people at risk of the illness. It is a “pretty sensitive topic” at this point, Mrazek explained, because “investigators are concerned that if someone is incorrectly labeled as vulnerable, it might have a negative impact on them.” However, he believes that genotyping people for alcoholism genes will eventually become a clinical reality. “I would think that the first group of people this would be appropriate for are the sons of alcoholics, because we know that they are at very high risk already. By knowing whether they did or didn't have an alcoholism gene, you wouldn't be surprising them with, 'Oh my gosh, I have some risk of developing alcoholism.'”

Genotyping to improve alcoholics' responses to treatment will probably also become clinically available. In fact, Kranzler envisions that it will be the first clinical application to emerge from alcoholism-gene discoveries, and Edenberg believes that such an application could come as early as five years from now.

For example, naltrexone, which is used to treat alcoholism, is known to be a μ-opioid receptor blocker. Also, variants in the OPRM-1 gene that make the receptor have since 2003 been known to influence patients' response to naltrexone. In other words, patients with one variant of the gene get a good response, whereas patients with another do not. So if patients learned that they had a form of the OPRM-1 gene that leads to a good response, they might be more likely to give naltrexone a try, Mrazek said.

Inevitably, as alcoholism-gene research progresses, it will lead to new and better treatments for alcoholism, experts agreed. “It's very possible that an alcoholism gene will be identified that represents a novel pharmacologic target, and this will have immediate treatment applications,” Gelernter predicted. “In this context I'd note that Antabuse [approved for the treatment of alcohol dependence] works by blocking acetaldehyde metabolism, mimicking the protective effect of having a nonfunctional ALDH gene. Genetics did not play a role in the development of this drug, but its alcoholism-gene connection suggests that genetics might play a role in the development of future alcohol-dependence medications.”

And perhaps a better treatment for alcoholism is already in the works in the inner sanctum of a pharmaceutical company, Mrazek speculated. The financial incentives to come up with one are gargantuan, he said. “I have heard that the cost of alcoholism to society is $300 billion [annually]. This is a gigantic number. If a drug company could find a medication that could minimize that cost even 10 percent, it would save $30 billion.”

Yet even if an effective drug for treating alcoholism becomes available, Kranzler cautioned, there will still be the daunting task of getting physicians to prescribe it and people with alcoholism to take it. After all, he pointed out, four medications have already been approved for treating the illness, and they are not used all that much. Nonetheless, he remains hopeful that as further research underscores the biological basis of alcohol dependence, it will galvanize both physicians and people with alcoholism to take advantage of drugs to treat the condition. ▪