Study shows gene candidates for predisposition

The meta analysis, which examined more than 4.5 million data points on more than 100 microarrays from mouse models, also identified more than 1,300 functional groups, including signaling and transcription pathways, which may also play an important role in establishing a capacity for a “high level of alcohol consumption.”

The results of the study could lead to a better understanding of the molecular mechanisms underlying the genetic propensity toward excessive drinking and point toward the development of new treatments for alcoholism.

The study, whose lead authors include INIA’s Megan Mulligan, Igor Ponomarev, and Susan Bergeson, was published April 17, 2006 in an advanced online version of The Proceedings of the National Academy of Sciences.

While the function of many of the 3,800 genes identified remains unknown, and could help determine potential levels of alcohol consumption, the study noted that the 75 genes with the largest changes fell into the broad categories of “cellular homeostasis and neuronal function.”

George F. Koob, Scripps Research professor, INIA west consortium leader, and participant in the collaborative study, says, “This fact suggests that differences in the ability to maintain or reset homeostasis and adjust neuronal function in the brain may underlie many aspects of an individual’s reaction to alcohol. It is possible that genetic expression differences could substantially affect developmental and adaptive brain neurocircuitry relating to alcohol preference, and that understanding these differences will be key to a better understanding of alcoholism.”

The study was careful to point out that although there is considerable similarity between the order of genes between genomes of mice and humans, any direct translation of the data is more likely to work on the pathway level rather than as exact mutations in specific genes.

“The molecular determinants of excessive alcohol consumption are difficult to study in humans,” Koob says. “So animal models for alcohol-related traits provide an important opportunity to explore mechanisms responsible for different aspects of what is a uniquely human disease. In particular, mouse models representing various levels of excessive drinking represent valuable tools to identify the genetic components of alcoholism.”

The mice used for the microarray analysis were not exposed to alcohol, however. The study defined only the transcriptional signatures of genetic predisposition to high and low levels of alcohol consumption. But the sheer number of differences in those signatures suggests clearly distinct brain pathways between mouse models with different levels of alcohol consumption, which could aid in finding new treatment solutions to the complex problem of alcohol addiction.

“The evidence from human and animal studies supports the hypothesis that alcohol addiction is a complex disease with both hereditary and environmental influences,” Koob says. “The meta-analysis of the microarray data, performed by Dr. Mulligan, Dr. Ponomarev, and Dr. Bergeson, clearly showed the complexity of the hereditary side of the equation by the fact that distinct mouse models with genetic predisposition for high levels of alcohol consumption have consistent and reproducible differences in brain gene expression.”

Ultimately, Koob says, the meta-analysis offers researchers a significant number of new targets for future study.

“The study led to identification of 20 candidate genes as regulators of alcohol preference that include some genes of unknown function,” Koob says. “The fact that we know so little about these genes and key functional groups revealed by our work indicates a rather widespread lack of knowledge about the molecular mechanisms driving alcohol consumption. In addition, the opportunity to study and understand these mechanisms through large-scale genomic screening approaches has not been fully exploited or explored. We hope that our work will help spur new, more expansive research.”

The project was led by Megan K. Mulligan, Igor Ponomarev, and Susan Bergeson of the Integrative Neuroscience Initiative on Alcoholism Consortium in collaboration with R. Adron Harris, Yuri A. Blednov, and Vishwanath R. Iyer of the Waggoner Center for Alcohol and Addiction Research and the University of Texas; Robert J. Hitzemann, John K. Belknap, Tamara J. Phillips, Deborah A. Finn, and John C. Crabbe of the Department of Veterans Affairs Medical Center and Oregon Health and Science University; Paula L. Hoffman and Boris Tabakoff of the University of Colorado Health Sciences Center; Nicholas J. Grahame of Indiana University School of Medicine; and George F. Koob of The Scripps Research Institute.