Alcohol tolerance 'switch' found

October 21, 2009

Researchers at North Carolina State University have found a genetic "switch" in fruit flies that plays an important role in making flies more tolerant to alcohol.

This metabolic switch also has implications for the deadly liver disease cirrhosis in humans. A counterpart human gene contributes to a shift from metabolizing alcohol to the formation of fat in heavy drinkers. This shift can lead to fatty liver syndrome - a precursor to cirrhosis.

In the study, published in the October print issue of the journal Genetics, the research team measured the time it takes for flies to stagger due to alcohol intake while simultaneously identifying changes in the expression of all their genes. They used statistical methods to identify genes that work together to help the flies adapt to alcohol exposure. In looking at corresponding human genes, a counterpart gene called ME1 was associated with alcohol consumption in humans, as people with certain variations of the gene showed a tendency to drink stronger alcoholic beverages.

Dr. Robert Anholt, William Neal Reynolds Professor of Biology and Genetics at NC State and the senior author of the study, says the research has possible clinical implications.

"Our findings point to metabolic pathways associated with proclivity for alcohol consumption that may ultimately be implicated in excessive drinking," he said. "Translational studies like this one, in which discoveries from model organisms can be applied to insights in human biology, can help us understand the balance between nature and nurture, why we behave the way we do, and - for better or worse - what makes us tick."
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Anholt conducted the study with Dr. Tatiana Morozova, a post-doctoral researcher in biology; Dr. Trudy Mackay, William Neal Reynolds Distinguished University Professor of Genetics; Dr. Eric Stone, an assistant professor of statistics; and graduate student Julien F. Ayroles. Researchers from Boston University's School of Medicine also contributed to the study.

The study was funded by a grant from the National Institute of Alcoholism and Alcohol Abuse, a unit of the National Institutes of Health.

Note: An abstract of the paper follows.

"Alcohol sensitivity in Drosophila: translational potential of systems genetics"

Authors: Tatiana V. Morozova, Julien F. Ayroles, Katherine W. Jordan, Laura H. Duncan, Mary Anna Carbone, Richard F. Lyman, Eric A. Stone, Robert R.H. Anholt, Trudy F.C. Mackay, North Carolina State University; Diddahally R. Govindaraju, R. Curtis Ellison, Boston University

Published: October 2009 in Genetics

Abstract: Identification of risk alleles for human behavioral disorders through genome-wide association studies (GWAS) has been hampered by a daunting multiple testing problem. This problem can be circumvented for some phenotypes by combining genome-wide studies in model organisms with subsequent candidate gene association analyses in human populations. Here, we characterized genetic networks that underlie the response to ethanol exposure in Drosophila melanogaster by measuring ethanol knock-down time in 40 wild-derived inbred Drosophila lines. We associated phenotypic variation in ethanol responses with genome-wide variation in gene expression and identified modules of correlated transcripts associated with a first and second exposure to ethanol vapors as well as the induction of tolerance. We validated the computational networks and assessed their robustness by transposon-mediated disruption of focal genes within modules in a laboratory inbred strain, followed by measurements of transcript abundance of connected genes within the module. Many genes within the modules have human orthologues, which provides a stepping stone for the identification of candidate genes associated with alcohol drinking behavior in human populations. We demonstrated the potential of this translational approach by identifying seven intronic SNPs of the Malic Enzyme 1 (ME1) gene that are associated with cocktail drinking in 1,687 individuals of the Framingham Offspring cohort, implicating that variation in levels of cytoplasmic malic enzyme may contribute to variation in alcohol consumption.

North Carolina State University

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