Addictive cocktail: Alcoholism and genetics

Research into the genetics of alcoholism has muddled along because of the complexity of the disease, but the project has led to a slew of new discoveries that may trigger more effective pharmacological solutions.

By Victoria Stagg Elliott, amednews staff. Feb. 5, 2001.

Mapping Disease
As the results of the Human Genome Project began to shake out into clinical applications, this 2001-02 series detailed progress in the prevention and treatment of a variety of diseases and conditions -- both on the near horizon and possibilities far into the future.

Twelve years ago, the Collaborative Studies on Genetics of Alcoholism, COGA, started its hunt for candidate genes that would indicate vulnerability to the disorder. Researchers began gathering data on more than 300 families with a high rate of problem drinking, thinking they would soon find the small group of genes at fault.

But the project, funded by the National Institute on Alcohol Abuse and Alcoholism, went nowhere fast. Instead, scientists quickly discovered that the disease was even more complicated than anticipated. It is polygenic and heterogeneous, and involved numerous environmental variables.

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"The end stage of alcoholism looks fairly similar, but there are many different ways to get there, so there are probably many different genetic causes," said Robert Karp, PhD, program director for genetics at NIAAA.

More than a decade later, researchers now have a better road map. They know to look on regions of chromosomes 1, 2, 7 and 11 for genes that make a person more likely to become an alcoholic. They also know to look to a region of chromosome 4 for a gene that might provide some protection against the disease.

These discoveries have been made only recently, sped along in part because of the Human Genome Project. Now, a specific gene linked to alcoholism may be announced before year's end.

"The Human Genome Project makes searching much easier than before," said Henri Begleiter, MD, the lead researcher of COGA and a professor of psychiatry with the College of Medicine at the State University of New York in Brooklyn. "COGA for a while was floundering. We had difficulties with a number of chromosomes where genes had not been placed. And now, as we better understand the genome, we are getting very close to finding something of interest."

One at a time

Before the Human Genome Project, scientists used the candidate gene approach. It had worked very well at finding the genes responsible for mendelian disorders or those caused by a single gene.

But this method was not as effective when it came to diseases caused by multiple genes that varied from person to person.

The one-at-a-time approach "was getting nowhere," said R. Adorn Harris, PhD, director of the Waggoner Center for Alcohol and Addictions Research at the University of Texas in Austin. "Alcoholism, schizophrenia -- these are some of the tough ones that are left. They really need a lot more genetic power to address them."

Researchers predict that the culprit genes -- when they find them -- will be responsible for disrupting the pleasure center of the brain. The question is how and where? It could be the genes responsible for the serotonin fibers that modulate the release of dopamine. It could also be the opioid nerve fibers that are also part of the system. Or both. Or neither.

"This is where it becomes complicated, and you need a genome project to help sort it out," said Gary Wand, MD, professor of medicine and psychiatry at Johns Hopkins University School of Medicine, Baltimore. "With the genome project, you don't even have to have a candidate gene. You have these quantitative trait loci where you have genetic markers, and you see how those genetic markers are inherited in alcoholics versus non-alcoholics. The power of the genome project is that there are going to be many, many more genetic markers. It'll be much more rarefied, and you can really start to pinpoint at the gene level."

Prevention

When COGA researchers began their effort, one of their goals was to develop a genetic screen that would allow for early intervention counseling and the possible use of preventive medication once it was developed.

"We used to think that if we knew what the genes were, then by doing various genetic tests on people very early in their lives we might be able to identify people at high risk for becoming alcoholics, and they could be counseled appropriately and maybe other types of preventive measures [could be used] as well," Dr. Karp said. "Based on everything we know today, that's probably not going to be a reachable goal anytime soon."

To a certain extent, genetics are already a part of prevention. A family history of the disease multiplies a person's risk for it significantly, and experts say patients should be warned of the dangers. A more sophisticated genetic test may be possible, but its use will be confounded by the multifactorial nature -- including nongenetic factors -- of the disease.

"I don't know if it will ever be practical to use genetic testing to identify people at high risk for alcoholism," Dr. Karp said. "It's going to be a long time before we have any genetic test that's better than the simple family history."

Treatment, researchers say, is the most likely area to benefit first. "Prevention is not where the strength or power is," Dr. Wand said. "I think the power really is in thinking about ways of using the genetics to better treat the disease."

Treatment

Treating alcoholism has long been tricky business and never a sure thing. Current pharmacological treatments are weak at best, and genomics could lead to drugs aimed at new targets or drugs tailored to the individual.

In September, researchers at the University of California at Los Angeles announced that heroin users with a variation of the dopamine D2 receptor (DRD2) gene responded poorly to traditional treatment. The gene -- nicknamed the pleasure-seeking gene -- is also implicated in alcoholism and other addictive behaviors.

"Using genotypes to match alcoholics to treatment -- that's a real potential for alcoholism," Dr. Harris said. "It's always been suspected to be heterogeneous, but it's difficult to define subtypes of alcoholics. A genetic definition would be quite useful, especially if it predicted which treatment would be useful."

DRD2 is not specific to alcoholism, and researchers expect that the genes discovered in the future will be unique to the disease.

"The bottom line is I think that alcoholism is distinct from other psychiatric disorders," Dr. Wand said. "One can have alcoholism and not suffer from any other comorbid disorder like depression or obsessive-compulsive disorder. But there will be some overlap."

Currently available drugs that treat alcoholism or alcoholism relapse are not very precisely targeted. Researchers hope that future discoveries will allow for more accuracy.

"We're now using medications that block opioid receptors, and they're not perfect at all," Dr. Wand said. "How the genetics will help us there is [that] right now we're blocking the subclass of opioid receptor that we know. But there could be many more receptor subtypes within that class. Maybe we're blocking the wrong receptors, and that's why we get a partial effect but not a complete effect."

Researchers, however, are quick to point out that genetics will never be the complete answer. Environment will complete the rest of the puzzle.

"This is a polygenic disorder," Dr. Wand said. "There are going to be several genes involved in creating a vulnerability. And that vulnerability is somewhere between 30% and 50%. The other 50% to 70% is environmental."

Understanding the environment

Genetics, however, also may solve the puzzle of which factors in a person's environment influence the development of alcoholism the most.

"We know of one factor in the environment that influences the risk for alcoholism, and that is how much alcohol you drink," Dr. Karp said. "No one's born an alcoholic. We're certain that there are other environmental factors that influence a risk for alcoholism, but we don't know what they are."

When an alcoholic's genetic profile is developed, screens could better select test subjects so research is not complicated by genetic variance.

"If we can identify the genes for alcoholism, then we can improve the design of studies to identify environmental factors," Dr. Karp said.

Great hope

The Human Genome Project is making a huge impact in research into alcoholism, but it is unlikely to impact how physicians treat or diagnose alcoholism anytime soon. Identifying the genes implicated in the development of alcoholism probably will come in the next few years, but understanding them will take longer.

Environmental factors need to be unraveled. And most expect the area likely to see the first impact to be pharmacological treatment.

"Every gene we identify as a possible risk for alcoholism is a potential target for development of a drug to either prevent or treat alcoholism," Dr. Karp said. "That's a source of great hope."

Research into the genetics of alcoholism has come a long way, but it also has a long way to go before information gained can be useful to the practicing physician.

"The job of finding genes is just the very beginning," Dr. Begleiter said. "Once you identify a gene, you have to understand its function. It's only after you fully understand its function that you can devise a rational treatment model. Before that you cannot. You can just take guesses."