Virginia Commonwealth University School of Medicine researchers have discovered a biological clue that could help explain why some drinkers develop a dependence on alcohol and others do not.
The findings move researchers closer to identifying those at risk for addiction early and designing better drug treatments to help people stop drinking.
About 18 million people in the United States have an alcohol use disorder, according to National Institutes of Health statistics. The vast majority go untreated.
“There are few and inadequate pharmacological treatments to help people who want to stop drinking, because this is a terrifically difficult human genetics problem,” said Jill C. Bettinger, Ph.D., associate professor in the Department of Pharmacology and Toxicology, VCU School of Medicine. “If we can better understand the molecular effects of alcohol, we can design more rational treatments and even warn people who are more susceptible to developing a dependence.”
Bettinger is the senior author of a paper, “SWI/SNF Chromatin Remodeling Regulates Alcohol Response Behaviors in Caenorhabditis Elegans and is Associated With Alcohol Dependence in Humans,” published Feb. 23 in the journal Proceedings of the National Academy of Sciences.
The paper describes how researchers examined the role of a protein complex - called switching defective/sucrose nonfermenting (SWI/SNF)—in determining the behavioral response of roundworms to alcohol.
Alcoholism and Genetics
Alcoholism can be passed down from parent to child, but not in the same way as Alzheimer’s or cancer. How exactly is it passed on?
In biology class, most of us were taught to believe that specific traits are passed on through our genes: if I have the “Alzheimer’s gene” or the “breast cancer gene,” there’s a probable chance that my son or daughter will carry that gene. However, what about more “complex” diseases like depression, or alcoholism? While alcoholism does tend to run in families - and has a genetic component - how exactly is it passed on?
In recent years, more and more studies are showing that there is another level of inheritance at work: epigenetics. Literally “above the genome,” epigenetic marks are chemical “tags” that can be put on or taken off DNA, and their purpose is to control the expression of genes. Some tags turn genes on, while others turn genes off. These tags come in the form of molecules called methyl groups or acetyl groups, and they can also appear on the outside of the DNA strand. In the nucleus of every cell, the very long strands of DNA coil around proteins called histones; these histones can be more “open” or “closed,” depending on what tags reside on the surface.
These “tags” can be helpful and are very important for many biological processes. For example, in the development of an embryo into a baby, epigenetics plays a huge role in making sure embryonic cells differentiate at the right time and place. Ever wonder how a small handful of cells become heart and lung and brain cells, and all the other cells in our bodies? Since every single cell contains all of our DNA, some genes have to be turned off, while others left on, in order for there to be different types of cells.
Researchers watched through microscopes as the tiny worms became drunk on ethanol, studying how their initial sensitivity to the alcohol and tolerance changed based on which genes were expressed within the SWI/SNF complex.
Because humans and worms have a similar genetic makeup, Bettinger then turned to Brien P. Riley, Ph.D., associate professor in the Departments of Psychiatry and Human and Molecular Genetics at VCU School of Medicine and co-author of the recently published paper. Riley is director of the Molecular Genetics Lab at the Virginia Institute for Psychiatric and Behavioral Genetics, where researchers have been studying the human genome and its relationship to the risk of illness or other traits.
Riley found that naturally occurring genetic variations in the same SWI/SNF complex so crucial to a worm’s tolerance were also associated with alcohol dependence in humans. Unlike Huntington’s and other diseases, which can be linked to a mutation in a single gene, the evidence suggests that the likelihood to develop alcoholism is the product of mutations in many genes, each with small effect. The SWI/SNF complex genes represent a piece of that puzzle.
Scientists have found that the genes which influence the amount of alcohol people drink may be distinct from those that affect the risk of alcoholism.
A large number of studies have focused on a genetic predisposition to alcoholism. They presume that the genes involved in this disorder, combined with environmental factors, influence susceptibility to alcohol dependence.
The various genetic pathways affecting alcohol drinking behavior have been investigated by Dr. Boris Tabakoff and his team at the University of Colorado-Denver using both rats and humans.
They compared genes involved in alcohol pathways in rats with human genes, using male study participants from Montreal, Canada and Sydney, Australia, to identify common genetic factors across species. Alcohol consumption among the participants ranged from abstinence to heavy intake, and drinking patterns were recorded.
The researchers discovered that drinking behavior is linked to the “pleasure and reward” pathways in the brain, and also to some of the systems that control food intake. In the journal BMC Biology, they write that the results emphasize the importance of looking at signaling pathways rather than single genes, and show cross-species similarities in predisposition to alcohol consumption.
“Our results also suggest that different genetic factors predispose to alcohol dependence versus alcohol consumption,” they add.
Dr. Tabakoff said, “We know that high levels of alcohol consumption can increase the risk of becoming alcohol dependent in those who have a genetic makeup that predisposes to dependence. This is a case of interaction between genes and environment.
“Indeed, in our study we found that higher alcohol consumption in humans was positively correlated with alcohol dependence. However, because different sets of genes seem to influence the level of alcohol consumption, as opposed to propensity for alcohol dependence, we are confronted with great variation in humans.”
Alcohol Consumption and Genetics
By Jane Collingwood
The findings also give researchers a perfect model moving forward in their studies.
“The identification of genes that are critical in the development of tolerance in model systems such as worms will lead to future progress in understanding human dependence on alcohol,” Riley said. “If the same effects are seen in worms, then it allows us to form and test a functional hypothesis about what kinds of changes lead to increased dependence risk in humans.”
Along with Bettinger and Riley, the paper’s authors include Laura D. Mathies, Ph.D., assistant professor in the Department of Pharmacology and Toxicology; Andrew G. Davies, Ph.D., assistant professor in the Department of Pharmacology and Toxicology; GinaMari G. Blackwell, laboratory and research specialist; Makeda K. Austin, research intern; and Alexis C. Edwards, Ph.D., assistant professor at the Virginia Institute of Psychiatric and Behavioral Genetics.
The research was funded by grants from the National Institutes of Health and the National Science Foundation.
Virginia Commonwealth University
Proceedings of the National Academy of Sciences