Diagnostics & Imaging Week

Alcoholism wrecks or severely impacts many lives in the U.S., from the alcoholic himself/herself to those around them: family, friends and co-workers.

But what if there were a way to test for genetic vulnerability to alcohol dependence and other substance abuse and use therapies that have been developed to prevent children, teenagers or adults from heading down a path that may have been genetically predetermined?

Researchers at the Molecular Neurobiology Branch of the National Institute on Drug Abuse (NIDA) of the National Institutes of Health (NIH; both Bethesda, Maryland) have conducted a study, completing "the most comprehensive scan of the human genome to date" linked to the ongoing efforts to identify people most at risk for developing alcoholism, the NIH said.

"Previous studies established that alcoholism runs in families, but this research has given us the most extensive catalogue yet of the genetic variations that may contribute to the hereditary nature of this disease," said NIDA Director Dr. Nora Volkow.

Elias Zerhouni, director of the NIH, said, "Tools such as pooled data genome scanning gives us a completely new way of looking at complex biological processes, such as addiction."

He added, "The ability to pinpoint genes in the human genome responsible for disease has the potential to revolutionize our ability to treat and even prevent diseases."

NIDA researchers found genetic variations clustered around 51 defined chromosomal regions that may play roles in alcohol addiction. The candidate genes are involved in "many key activities," the NIH said, including cell-to-cell communication, control of protein synthesis, regulation of development and cell-to-cell interactions.

For example, according to the NIH, one gene implicated in the study, the AIP1 gene, is a known disease-related gene expressed primarily in the brain, where it helps brain cells set up and maintain contacts with the appropriate neighboring cells.

The NIH said, "many of the nominated genes have been previously identified in other addiction research," which "provides support to the belief that common genetic variations are involved in human vulnerability to substance abuse."

The research, led by Dr. George Uhl, a scientist with the NIDA, also is "one of the first" studies to show that addiction may be linked to memory pathways in the brain vs. what has been commonly thought of as related to reward pathways in the brain in recent years.

Uhl said the research related in a general sense to the genetic architecture, and it found that "there are common variants that are not rare in the general population [to which] we can attribute the addictive disorder."

"If you compare these [variants] to data from other addictions, there's a lot of overlap between the genetic underpinnings of alcoholism and the abuse of other substances," Uhl told Diagnostics & Imaging Week, adding that no one gene seemed to play that large a role, so it could be called a "polygenic disorder," or disorder contributed to by multiple single nucleotide polymorphisms, or SNPs.

However, more studies are planned, with some very interesting long-term possibilities for developing genetic tests and prevention programs and therapies – including the concept of personalized medicine – which could result from long-term studies, he said.

"The amount of data from these individuals [in the study] is tremendous, but it doesn't really saturate all of the possibilities," Uhl said. "We're trying to get funding to look at higher-density SNP markers that can cover more of the genome."

This most recent study covered "about half of the genome," in looking at the way alcoholism relates to other addictions, such as nicotine dependence, or methamphetamine dependence or dependence on illegal drugs.

One of the goals for the research is to develop genetic tests using the data ultimately gathered, and toward this end, the NIH is working with Affymetrix (Santa Clara, California) toward developing such a microarray or gene chip. According to Uhl, Affymetrix has "already validated on one of these commercial chips" a test for the addiction vulnerability.

"They did SNPs on a chip at a cost that is probably within range of a clinical test," he said.

Once this type of substance addiction "vulnerability" can be tested, the goal is to use the data to learn which drug therapies work best for which individuals.

Ultimately, the goal would be to focus efforts on drug prevention by knowing an individual's genetic makeup vs. the millions of dollars now spent focused on moving those dependent on alcohol to abstinence.

"The eventual goal of some of this is a better understanding to make [substance abuse] a more clinically tractable disorder on a larger scale, because … there are many, many dollars invested in the U.S. in prevention and treatment, and not all of these are highly efficacious to put it modestly."

One of the important results from research such as that by Uhl and his colleagues, with the knowledge that substance abuse may be dominated by memory pathways, is to develop markers to "understand why some of these people have a substantive grip on the substance memories in what that might help individualized treatment strategy.

"Even with all the vulnerability genes, nobody has to become an alcoholic," but a better spend on resources could focus on "those people most at risk," Uhl said.

One critical key to all of this being possible are resolving "issues of genetic privacy, confidentiality and insurability that if they are worked out in the right context would be very powerful tools," he said.