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Genes' Influence on Alcoholism Investigated

New, powerful gene hunting techniques hold promise for scientists pursuing the genes involved in complex diseases. This was the topic of a recent 2-day conference, "Genes and the Environment in Complex Diseases: A Focus on Alcoholism," sponsored by the National Institute on Alcohol Abuse and Alcoholism.

Finding the gene variants involved in alcoholism is the primary focus of NIAAA's Collaborative Study on the Genetics of Alcoholism (COGA), a large-scale research program based in six research centers located across the United States. At these centers, people with histories of alcoholism and their families are being extensively studied. Dr. Henri Begleiter, State University of New York, reported that, as of January 1997, a total of 9,946 people had been recorded into COGA's database.

A serious drawback in identifying the traits and characteristics associated with alcoholism is the fact that a common definition of this disease does not exist. As noted by NIAAA director Dr. Enoch Gordis, a clear description of the phenotype of alcoholism is essential to accurately identify people at greatest risk for disease. Once the phenotype(s) has been defined, it can be linked to genetic markers. COGA scientists are working to better define alcoholic phenotypes and, according to Dr. Victor Hesselbrock, University of Connecticut, four different classes of alcoholism thus far have been identified.

A person's response to alcohol appears to be one of the strongest predictors of future alcohol problems and, thus, a potentially useful marker for studying the genetics of alcoholism. Dr. Marc Schuckit, University of California, discussed findings from the COGA project which showed that sons of alcoholics had lower responses to alcohol (i.e., they needed to drink more alcohol to experience an effect). The COGA data augment earlier findings showing that children from alcoholic families may have an innate tolerance to alcohol that, when combined with certain environmental factors, could put them at greater risk for alcoholism.

In developing a whole genome screen, COGA has typed 291 markers in about 1,000 subjects, according to Dr. John Rice, Washington University School of Medicine. To date, he reported, the middle of chromosome 1 consistently has been implicated in alcoholism using two different disease definitions and two analytical methods. Other chromosomes with possible evidence of linkage include 4, 7 and 16. The next step will be to confirm the current findings using a second sample of 1,000 subjects. For those linkages that are confirmed, investigators will attempt to narrow the region of interest on each chromosome using additional markers and then examine these regions on a molecular level to identify the genes influencing alcoholism.

Before a potential gene's function can be positively linked to alcoholism, however, other factors must be considered. Gene-environment and gene-gene interactions are ubiquitous. As noted by Dr. John Blangero, South West Foundation for Biomedical Research, a gene may not have an effect unless another gene is present, or a gene may have only a small effect on its own but a large effect when combined with other genes. Scientists currently are developing powerful statistical methods to more clearly discern each gene's effect and to take into account gene-gene and gene-environment interactions.

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