Linking alcohol drinking patterns to specific genes

October 15, 2002

Researchers now know that alcoholism, like many other complex disorders, involves genetic vulnerabilities but they still do not know what specific genes might be involved. Adding to the challenge of genetic research is the variability in subgroups of alcoholics, variations that include differences in severity of dependence, levels of familial alcoholism, personality traits, and coexisting psychopathologies such as anxiety, depression, and antisocial behavior. A study in the October issue of Alcoholism: Clinical & Experimental Research examines drinking patterns and related behaviors among alcoholics and nonalcoholics in order to develop quantitative phenotypes, which are subsequently examined for genetic influence.

"We were not simply looking for ways of characterizing people with alcoholism, but rather we were looking for different drinking patterns among individuals who had a variety of drinking behaviors - ranging from social drinkers to alcoholics," explained Danielle M. Dick, postdoctoral fellow in the Department of Medical and Molecular Genetics at Indiana University School of Medicine and lead author of the study. "Studying quantitative drinking patterns among a wide spectrum of drinkers, rather than focusing solely on alcoholics, may provide a helpful way to identify genes involved in alcohol use and problematic drinking. When we examined combined characteristics of individuals' drinking behavior, associated problems, and personality, we found evidence that a gene on chromosome 1 may be related to patterns of drinking that coincide with higher anxiety-type behavior."

There were four steps of data analysis for this study. First, researchers established baseline 'profiles' of drinking and related behaviors of the more than 9,000 participants (individuals from alcoholic and nonalcoholic families) in the Collaborative Study on the Genetics of Alcoholism (COGA). Next, they examined an initial sample of the COGA participants (n=987) for their genetic make-up, linking their genotypes to the previously created profiles. Third, they repeated the previous step with a different and larger sample of COGA participants (n=1295) in order to reaffirm their findings. Lastly, they combined the initial and replication samples and performed a combined analysis.

"There is a moderate level of novelty to the overall approach used in this study," said Kenneth Kendler, Banks Distinguished Professor of Psychiatry and professor of human genetics at Virginia Commonwealth University. "Instead of taking categorical diagnoses, which have been the major emphasis of most such analyses, they look at quantitative indices. This has been attempted in the area of schizophrenia, for example, in which people have looked at 'symptom counts.' The premise is that the categorization that we've used for clinical purposes, that physicians have used for a long time, may not always be optimal for these kinds of genetic studies. I happen to think that's likely the case, but we don't know that definitively."

Building upon their data analysis, researchers constructed three phenotypes, which accounted for 68 percent of the variance. Phenotype 2 - associated with a later age of onset of regular drinking and higher harm avoidance - provided the strongest evidence of linkage with chromosome 1 and, to a lesser degree, chromosome 15.

"The importance of our findings is that they potentially bring us closer to identifying genes involved in patterns of drinking behavior," said Dick. "Identifying these genes should eventually lead to early intervention for individuals at risk for alcoholism due to the inheritance of susceptibility genes, and lead to the development of more effective treatment of alcoholic patients. The study is also important for the field of alcohol studies because it demonstrates the importance of studying quantitative measures of drinking, and drinking patterns among all drinkers, rather than focusing solely on alcoholics."

"All of the genes that influence Mendelian traits, that is, disease genes that always result in an illness, have been found," said Kendler. "Now the cutting edge of medical genetics is in the genetics of complex traits, where the task is much more difficult because the phenotypes themselves don't have clear boundaries, the disorders are likely quite complex and involve multiple genetic systems, and it's very likely that the genes interact with each other and with the environment. These are hard problems, and this study makes a modest, potentially incremental advance in this difficult area."
Co-authors of the Alcoholism: Clinical & Experimental Research paper included: Tatiana Foroud, John Nurnberger, Jr. and Howard J. Edenberg of Indiana University School of Medicine; Alison Goate, John Rice and Kathleen K. Bucholz of Washington University in St. Louis, Missouri; Ray Crowe and John Kramer of the University of Iowa; Marc A. Schuckit and Tom L. Smith of the University of California - San Diego; Bernice Porjesz and Henri Begleiter of State University of New York; and Victor Hesselbrock of the University of Connecticut. The study was funded by the National Institute on Alcohol Abuse and Alcoholism.

Alcoholism: Clinical & Experimental Research

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