Previous research has extensively studied the association of the dopamine D2 receptor gene (DRD2) with alcoholism. Findings, however, have been inconsistent. A new study suggests that a neighboring gene called ankyrin repeat and kinase domain containing 1 (ANKK1) may also be involved in addictive behaviors.
"Previous inconsistencies could be due to a variety of sources, including differences in the symptom profiles of alcoholics who have participated in various studies, and/or methodological limitations of previous studies," explained Danielle Dick, corresponding author for the study.
"If individuals are not carefully matched, and/or differ on other characteristics such as ethnicity, then the gene frequency could differ because of those factors rather than as a function of disease status. Another limitation of previous studies is that they have largely focused on a single genetic marker in the DRD2 gene, which we now know is actually in the neighboring ANKK1 gene." Now at Virginia Commonwealth University, Dick was an assistant professor at Washington University, St. Louis when this study was conducted.
Dick said that this study addressed several of these previous limitations, providing a step forward in the research on genetic influences on addictions. Research, commented Brien Riley, director of the molecular genetics lab at Virginia Commonwealth University, that nonetheless remains unclear despite huge advances in understanding the genetic makeup of humans.
"Previous evidence indicates that genes play a major role in liability to addictions, including alcoholism," said Riley. "Yet genes are certainly not sufficient to produce disease by themselves. The individual must be exposed to alcohol, which, in common with any chemical encountered in the world, is explicitly environmental. When you consider that addictions also involve that incredibly complex and unpredictable thing that is human behavior, then the real complexity of the problem is clear."
Riley explained that genetic research can often be guided by additional non-genetic information. "We know that certain regions of the brain are particularly important in processing reward," he said. "Neurons which use dopamine as their neurotransmitter connect these regions, and some research suggests that there may be dopamine imbalances in these regions among alcoholics. Although these differences might be the result of chronic heavy drinking rather than its cause ... variation in genes coding for the various proteins that mediate dopamine neurotransmission might also be involved in alcoholism. The DRD2 gene, which codes for one of the five dopamine receptors, has been heavily studied for possible links to alcoholism, but with mixed results. Hence the current study."
Using data collected as part of the Collaborative Study on the Genetics of Alcoholism (COGA), a long-term project with multiple sites across the United States, researchers genotyped 26 single-nucleotide polymorphisms (SNPs) spanning DRD2 and ANKK1 in a sample of 219 Caucasian families (n=1923).
"The key finding here is that when you genotype markers not just in DRD2, the highly studied gene in this region, but also genotype markers across surrounding genes, there is evidence that surrounding genes, such as ANKK1, may also be involved in addiction phenotypes," said Dick. "If there are indeed multiple genes in the region involved, it may help explain the inconsistency surrounding whether DRD2 plays a role."
Riley concurs. "The study finds strongest evidence of association not in the DRD2 gene, but rather in the neighboring gene, ANKK1," he said. "This is notable because it suggests that the original evidence pointed to ANKK1 all along and it was the error in mapping the variant that supported the involvement of DRD2. However, the evidence in this paper is by no means conclusive that ANKK1 is involved in alcoholism, any more than the older evidence was that DRD2 was involved, and it must be interpreted with caution and further explored."
Which is the plan. Dick and her COGA colleagues will continue to pursue the identification of additional genes involved in genetic susceptibility to alcoholism, across this and several other chromosomal regions.
Results are published in the October issue of Alcoholism: Clinical & Experimental Research.
Co-authors of the ACER paper, "Family-Based Association Analyses of Alcohol Dependence Phenotypes across DRD2 and Neighboring Gene ANKK1," were: Jen C. Wang, Jevon Plunkett, Fazil Aliev, Anthony Hinrichs, Sarah Bertelsen, John P. Budde, Elianna L. Goldstein, Daniel Kaplan, Laura Jean Bierut, and Alison Goate of Washington University in St. Louis; Howard J. Edenberg and John Nurnberger, Jr. of Indiana University School of Medicine; Victor Hesselbrock of the University of Connecticut Health Center; Marc Schuckit of the University of California, San Diego as well as the VA Medical Center, San Diego; Sam Kuperman of the University of Iowa College of Medicine; Jay Tischfield of Rutgers University; and Bernice Porjesz and Henri Begleiter, now deceased, of SUNY Health Science Center at Brooklyn. The study was funded by the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse.
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