Chromosome Four Contains Genes That Affect Drinking Behaviors In Smokers

"It is commonly observed that people that drink also smoke and vice versa," explained Kirk C. Wilhelmsen, associate professor in the departments of genetics and neurology at the University of North Carolina as well as corresponding author for the study. "This suggested to us that families selected for smoking behavior would also have an increased incidence of drinking behavior."

"Twin studies of alcohol consumption have a long history and were the first to suggest the importance of genetic factors in alcohol use and alcoholism," added Gary E. Swan, director of the Center for Health Sciences at SRI International and also an author of the study. "The identification of linkages between specific genomic regions of interest and alcohol use and abuse is an area of science that has been active for about seven years. A consistent finding from these studies is the linkage between a region of chromosome four containing several genes that produce enzymes involved in the metabolism of alcohol and families with a high frequency of alcohol abuse."

Using data collected in an ongoing interdisciplinary study of environmental and genetic determinants of tobacco use conducted at the Oregon Research Institute under the direction of Dr. Hyman Hops, another author of the study, researchers examined 158 nuclear families that were determined to have at least two first-degree relatives who had smoked 100 or more cigarettes in their lifetime. Genotypes were determined from blood DNA taken from each family participant and analyzed for linkages to selected phenotypes.

"We looked for chromosome regions that had genes that affect patterns of drinking behavior," said Wilhelmsen. "The locations with the strongest evidence were the same places that were previously found in other linkage studies looking for loci that affect alcoholism, although we found evidence that these loci affect drinking behavior less severely than for alcoholism." Wilhelmsen is referring to one locus on chromosome two, and two loci on chromosome four.

"These findings are significant because the families in this study were selected by virtue of their use of tobacco rather than for excessive drinking and alcoholism, which have been the selection traits in previous linkage studies," said Swan. "Furthermore, the consistency of this result across study samples strongly suggests that variations in genes for alcohol metabolism play a role in determining who will go on to regular consumption of alcoholic beverages after initial exposure, and who is at risk for alcoholism."

"Our work provides evidence that variations in genes in a particular region affect drinking behavior," said Wilhelmsen, "which will encourage further work to identify the genes that are involved. When these genes are identified, and their normal function deduced, we will have a better understanding of the biology of drinking behavior. This may lead to new therapeutic approaches to treat alcoholism."

Swan concurs, however, he said that the study is suggestive rather than conclusive. "As with all studies of this sort, the findings need to be confirmed in other, nonclinical samples," he said. "The reader should also know that many genes are likely to be involved in alcoholism, and that genetic effects most likely interact with the effects of the environment to increase risk for alcohol abuse. The overall genetic signal observed in this study was modest which suggests the presence of other factors, both genetic and environmental in nature."

Wilhelmsen said that he and his colleagues have already begun to systematically search for DNA sequence changes in the same chromosome regions that affect drinking behavior.

Swan suggested that future research also include certain biological or physiological measures in the assessment of families. "This will help to more directly quantify alcohol metabolism along with specific measures of environmental risk such as stress," he said. "These measures can then be examined in linkage analyses to test the hypothesis that a metabolic substrate determines alcohol consumption and that environmental factors mediate the effects of genetic factors."

Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, "Support for Previously Identified Alcoholism Susceptibility Loci in a Cohort Selected for Smoking Behavior," were: Li S-C. Cheng of the City of Hope National Medical Center; Christina N. Lessov-Schlaggar, Karen S. Hudmon, and Huijun Z. Ring of the Center for Health Sciences at SRI International; Christopher Amos of UT M.D. Anderson Cancer Center; Heidi S. Feiler of the Department of Neurology at Gallo Institute; Judy A. Andrews, Elizabeth Tildesley and Hyman Hops of the Oregon Research Institute; and Neal L. Benowitz of the Division of Pharmacology at the University of California San Francisco. The study was funded by the University of California Tobacco-Related Diseases Research Program and the State of California. (Funding for the initial study was provided by the National Institute on Drug Abuse.)