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Alcoholism's Genetic Roots Becoming Clearer

Twenty-six genes, or at least genetic material close to them, appear to be implicated in alcoholism. The strongest candidates have been linked with other types of substance abuse as well.

The largest dragnet for alcoholism genes conducted to date has produced quite a catch, according to the National Institute on Drug Abuse (NIDA).

The scientific trawl, headed by George Uhl, M.D., Ph.D., chief of NIDA's Molecular Neurobiology Research Branch, has identified 188 variants in genetic material located at 51 different sites that may contribute to alcoholism.

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

Many of the 188 variants in genetic material are located near or even with in 26 known genes. For example, three of the variants that cluster on chromosome 7 are located very close to the AIP1 gene. This gene is expressed primarily in the brain, where it interacts with atrophin and other proteins. Three of the variants, on chromosome 7, lie within the flank of the gene that codes for the receptor for neuropeptide S, which is thought to be an important modulator of wakefulness and anxiety. Four of the variants, located on chromosome 3, reside within the gene that makes the angiotensin II receptor.

Moreover, a number of the genetic variants have already been linked with alcoholism in previous research. In fact, some of the variants also seem to predispose to other kinds of addiction, regardless of ethnic background.

For example, four of the variants fingered in this study are located very close to putative addiction genes identified in both European-American and African-American polysubstance abusers. One of the variants identified in this inquiry flanks five supposed addiction genes taken from methamphetamine-dependent Japanese.

This level of replication is "extremely remarkable," Uhl and his team asserted in their research paper, which is in press with the American Journal of Medical Genetics.

Of the variants he and his group have linked with alcoholism, Uhl told Psychiatric News that those apparently playing the largest role in the illness "also have evidence for association with methamphetamine abuse (manuscript under review) and illegal substance abuse (manuscript in press in Neuropsychiatric Genetics)."

Uhl said researchers were surprised to find that many of the candidate alcoholism genes they have identified border genes that make cell-adhesion molecules. "Neurons and glia grow, form, and maintain close contacts with each other during development and in adulthood based on these cell-adhesion molecular processes," he explained.

The DNA samples that Uhl and his team used in this investigation were collected through the Collaborative Study on the Genetics of Alcoholism (COGA) during the 1990s (Psychiatric News, March 5, 2004).

The scientists used a technique to identify alcoholism genes that, as far as they know, has not previously been used for this purpose. Called association genome scanning, it can identify smaller chromosomal regions than more traditional gene-identification techniques. Another advantage is that it can pool Dna samples, which preserves confidentiality and reduces costs.

The study was funded by the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism.

"Pooled Association Genome Scanning for Alcohol Dependence Using 104,268 SNPs: Validation and Use to Identify Alcoholism Vulnerability Loci in Unrelated Individuals From the Collaborative Study on the Genetics of Alcoholism" will be posted at <www.interscience.wiley.com/jpages/0148-7299>.

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