Sunday, June 29, 2014
Boozy Genes—The Making of an Alcoholic?
The more we learn about the genetics of alcoholism, the clearer it becomes that evidence-based treatment should become the norm.
Alcoholism has long been known to run in families. In fact, based on previous twin studies, more than 50% of the overall risk can be attributed to inheritance. This suggests that genetics plays a role. But, how?
Over the past 20 years, scientists have leveraged new genetic—and genomic, or whole-genome—technologies to discover some of the major genetic variants associated with alcoholism. Since 1989, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) has funded the Collaborative Studies on Genetics of Alcoholism study, or COGA—a US-based, multi-site study involving many researchers—with the hope of identifying the specific genes that contribute to the susceptibility to developing alcoholism. And, while the study has found a significant handful of genes, the take-away is that alcoholism is not only a complex disease—many genes, each contributing a small effect—but a heterogeneous one: there are different “types” of alcoholism, and each one is defined by one’s personal genetic makeup, or genotype.
Every alcoholic’s story is, in fact, unique. And, science is beginning to back up this idea of multiple pathways to the same disease.
Says Howard Edenberg, a professor of biochemistry and molecular biology at the Indiana University School of Medicine and one of the principal investigators on COGA, “It’s most critical to start any discussion [of the genetics of alcoholism] with the clear understanding that we’re not dealing with a single-gene disease,” he says. “We’re dealing with a complex genetic disease in which there’s good evidence that…no one gene is determinative.”
Additionally, alcoholism does not have one cause, and it is not entirely genetic—environment and personality play a large role in whether someone will develop a substance use disorder of any kind, including one with alcohol. However, understanding that some people are, in fact, more sensitive to drinking alcoholically than others, scientists are aiming to both determine what makes them more vulnerable and how to better treat people based on their genetic makeup.
Decades ago, scientists observed that some East Asians—people of Chinese, Japanese, Vietnamese, or Korean descent, among others—became “flushed” when they drank. This so-called “Asian flush” experienced by between 40 and 50 percent of East Asians has since been attributed to a mutation in a gene that metabolizes alcohol. When the by-product of the breakdown of alcohol, called acetaldehyde, builds up in their bodies, they experience an uncomfortable sensation of warmth, rapid heart rate/palpitations, and nausea and/or weakness. Researchers traced this to the ALDH1 gene, the enzyme that breaks down alcohol into acetaldehyde. In small doses, one feels hung over; in large, as with Asians with this specific gene variant, it can be toxic. Needless to say, this gene acts to protect one against alcoholism, for some lending an up-to-six-fold decreased risk.
Out of over 11,000 people interviewed and tested, COGA chose to study 262 families that had two or more first-degree relatives of the patient diagnosed as alcohol-dependent. The study—which used genomics tools like linkage analysis, genome-wide association studies (or, GWAS), and candidate gene studies—identified two genes involved in the metabolism of alcohol (aldehyde dehydrogenase ALDH2 and alcohol dehydrogenase ADH1B) that have the strongest effect on the risk of alcoholism. Significant linkages were found on chromosomes 1, 2, 4, and 7, and later, several more genes were localized, including ADH4 and GABRA2 on chromosome 4, and CHRM2 on chromosome 7. Studies continue to reveal other genes, and with increasingly large sample sizes afforded by meta-analyses, entire biological pathways are beginning to be elucidated.
GABA, or gamma-aminobutyric acid, is the most common inhibitory neurotransmitter in the human nervous system. Mutations in the receptor for this protein, called GABRA2, affect GABA’s function. As seen in many substance use and other psychiatric disorders including alcoholism, decreased GABA function could lead to increased impulsivity. CHRM2 is a gene that makes a specific receptor for acetylcholine, another common neurotransmitter controlling neuronal excitation levels in the brain.
Every alcoholic’s story is, in fact, unique. And, science is beginning to back up this idea of multiple pathways to the same disease. An added prospective arm to the COGA study followed teenagers as they grew up, and those with the ADH gene mutation became early drinkers, whereas those with the CHRM2 risk gene were more apt to be depressed and those with the GABRA2 variant showed more trouble with conduct problems. “The ADH risk variants may contribute to the development of alcoholism directly by promoting heavy drinking, whereas the GABRA2 variants predispose a person to conduct problems, which are themselves a risk factor for alcoholism,” writes Indiana University’s John Nurnberger, Jr., an investigator on COGA, in an article for Scientific American in 2007 (with co-author and COGA researcher Laura Bierut of Washington University). “Meanwhile CHRM2 may act through depression and other internalizing symptoms to foster drinking.”
A recent study adds to the multiple-pathways idea. In a paper appearing in Translational Psychiatry in May, a research team from the United States and Germany led by Alexander Niculescu, III, used a computational approach to discover genes involved in alcoholism. The group narrowed a larger group of associated genes down to a panel of 11, which were then shown to be able to be used to differentiate between alcoholics (and alcohol-dependents) and controls in three independent test cohorts. Niculescu grouped these genes into three “behaviorally relevant” categories—including anxiety, mood, and cognition—which put them into a broader “mindscape-dimensional” view of genes involved in alcoholism and other major psychiatric disorders.
One of the genes that falls into both the anxiety and cognition category is the DRD2 gene, which makes a dopamine receptor molecule. DRD2 has also been studied as a possible target for personalized treatment.
“Rather than thinking of targeting particular genes, you may be able to target [a] pathway,” Edenberg says, citing a good example unrelated to alcoholism as being the discoveries made surrounding statins, which influence one enzyme but affect cardiovascular disease as a whole by targeting cholesterol production. “If we get a better understanding of the mechanisms behind disease, we will be in a much better [place] to both design and target therapy.”
Unfortunately, the idea of one gene causing alcoholism is nothing more than a myth. A study from a consortium of five UK universities riled up the mainstream science media last fall, encouraging headlines that touted the discovery of an “alcoholism gene.” What co-lead author Quentin Anstee’s lab at Newcastle University found was that mice with a genetic mutation in the GABRB1 gene “overwhelmingly preferred” drinking alcohol over water. While it’s an astonishing finding in mice, humans are much more complex and influenced by myriad environmental factors—which themselves impact the function of many interconnected genes, proteins, and processes.
PERSONALIZED MEDICINE BASED ON GENETIC TESTING
It’s becoming more likely with every discovery that alcoholism—like cancer, for instance—is a heterogeneous disease, meaning that while it looks similar on the outside, it’s actually many different conditions on the inside. In fact, several recent studies have verified that different genetic “types” of alcoholism exist—patients respond differently to the same medication based on their genetic makeup and its effect on how they metabolize the drug (a field known as “pharmacogenetics”). According to a recent review in CNS Drugs, three particular genes—the μ-opioid receptor, the dopamine D4 receptor, and the serotonin transporter gene—have shown the most promise in recent studies as targets for personalized therapy using available drugs for alcoholism (naltrexone and acamprosate, as well as off-label drugs sertraline (Zoloft), olanzapine (Zyprexa), and ondansetron).
In one of the first pharmacogenetic studies, published in early 2011 in the American Journal of Psychiatry, alcoholics were divided into treatment groups based on a specific mutation in their serotonin transporter gene. Mutations in this gene have been linked to many conditions, including not just alcoholism, but depression, obsessive-compulsive disorder, romantic love, hypertension, and generalized social phobia. Those with two specific mutations were better able to reduce their number of drinks on drinking days and their total number of drinking days using the drug ondansetron, a serotonin-3 receptor antagonist typically used to treat nausea and vomiting. Other groups, namely David Goldman’s lab at NIAAA, are studying this specific receptor subtype, also known as the 5-HT3 receptor.
“[The] work on the serotonin transporter and serotonin-3 receptor genotypes is [the] most promising,” says Bankole Johnson, chairman of psychiatry and professor of neurobiology at the University of Maryland School of Medicine and the 2011 study’s lead author. Current research out of Johnson’s lab include a clinical trial entering phase III examining the effectiveness of low-dose ondansetron and a study to examine the effects of naltrexone and acamprosate on liver and kidney function in alcoholics.
Several studies have found specific genotypes to be associated with a better response to naltrexone; in particular, alcoholics with a specific variation of an opioid-receptor gene have a lower rate of relapse than those with a different variation. Naltrexone, an opioid receptor antagonist, works by blocking the opioid receptors—and therefore, the high that drinking alcohol triggers. Other studies are looking at how specific genotypes—mutations in certain genes—affect the way in which alcoholics metabolize disulfiram (Antabuse) and topiramate (Topamax), to name a few.
Just how far are we from being able to hand an alcoholic a genetic test and use this to determine the most personalized—and effective—treatment? It’s still the early days, Edelman says, who doesn’t think “we’re going to be doing genetic testing in terms of prevention work in the foreseeable future.” Genetic testing services, especially direct-to-consumer ones that also typically delve into ancestry genes, offer far from a complete picture. Even if you have a protective version of some gene, there could still be plenty of genes that influence the tendency toward alcoholism that have yet to be discovered.
Still, genetic testing will be “of critical importance,” when it comes to treatment options in the near future, Johnson says. “Alcohol dependence is heterogeneous. Therefore, treatments that target each of the various subtypes will be far more successful than one-size-fits-all. The future is genetic testing to determine who might respond to a particular medication, which [alcoholics] can then be given.”