Howard J. Edenberg, Ph.D.
Indiana University School of Medicine
Alcoholism: Clinical & Experimental Research
"There are braking neurotransmitters and accelerating neurotransmitters," said Jaakko Lappalainen, assistant professor of psychiatry at Yale and first author of the study. "GABA is one of the braking neurotransmitters, it brakes the neurons so that they don't get out of control." Activating or enhancing the function of GABA receptors usually decreases activity in brain neurons and can decrease activity of the entire brain and body, as occurs in general anesthesia. Some of alcohol's effects appear to be mediated through GABRA2, however, this only explains part of the development of alcohol dependence.
"Alcoholism is a complex disease, and an individual's vulnerability is affected both by the set of genes they inherit, and the environments they are exposed to, including their behaviors," said Howard J. Edenberg, Chancellor's Professor and professor of biochemistry and molecular biology, and of medical and molecular genetics, at the Indiana University School of Medicine. "No one gene 'makes' one an alcoholic. But it is important to discover the variations in individual genes that affect one's risk for the disease. This will improve our ability to prevent and treat the disease."
For this study, researchers recruited 113 Russian alcohol-dependent men from a St. Petersburg treatment center, as well as 100 local military personnel as controls. Blood samples were drawn from all participants and genotyped for seven GABRA2 single nucleotide polymorphisms (SNPs).
"SNPs are variations in the genetic code," said Lappalainen. "A person's DNA is made of base pairs; about every 100 base pairs, there is a variant that is different between individuals. We believe that a lot of the variation in the way we look, behave and respond to medications is encoded in variant sites in genes."
Lappalainen and his colleagues found significant associations between two SNPs and alcohol dependence. Furthermore, comparison of these findings to those of the U.S. population suggests that the structure and frequencies of GABRA2 haplotypes (a group of variations that are inherited together) are very similar in U.S. and Russian populations.
"These findings help demonstrate," said Lappalainen, "that regardless what different environmental factors in Russia may be in play, compared to the U.S., GABRA2 still seems to be influencing risk in that population."
Edenberg concurs. "This paper lends further support to the finding, initially reported by the Collaborative Study on the Genetics of Alcoholism (COGA), that variations in the GABRA2 gene affect risk for alcoholism," he said. "The COGA finding was also supported by a case-control study. Although the data from the current study are not as strong as the earlier reports, the consistency of support for the finding is important. It is notable that the three studies," he added, "with different study designs, all point to the same region of the same gene, making the accumulated evidence even stronger. It is exciting that this finding has been replicated and extended to a different population."
Nonetheless, both Lappalainen and Edenberg pointed out that possessing the GABRA2 gene, which is very common, does not mean an individual will become an alcoholic.
"It is important to emphasize that this is not 'the gene for alcoholism'" said Edenberg. "There is no such thing. It is one of several in which variations contribute to the risk. COGA has already identified additional genes, including GABRG3 and CHRM2, and has evidence for additional genes. It is also critical to make clear that having any one gene variant, or even a collection of genes that increase risk, does not condemn someone to being an alcoholic; the genes affect the risk, but so do the choices made by the individual. This is similar to diabetes, in which genes affect risk but so does behavior such as eating and exercise."
Lappalainen said he is planning future studies on associations between the GABA system and addiction, particularly the mechanisms of how genes may actually increase the risk of developing alcoholism.
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, "Association Between Alcoholism and GABRA2 in a Russian Population," were: Evgeny Krupitsky, Mikhail Remizov, Sofia Pchelina, Anastaisa Taraskina and Edwin Zvartau of the St. Petersburg State Pavlov Medical University in Russia; Lucia K. Somberg, John H. Krystal and Joel Gelernter of the Department of Psychiatry at Yale University School of Medicine, and the VA Connecticut Healthcare System; and Jonathan Covault and HenryR. Kranzler of the Department of Psychiatry at the University of Connecticut School of Medicine. The study was funded by the National Institutes of Health, the Alcoholic Beverage Medical Research Foundation, the U.S. Department of Veterans Affairs, and the Ethel F. Donaghue Women's Health Investigator Program at Yale.
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