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Alcohol dependence, psychiatric disorders share genetic links

Key alcoholism gene influences how quickly body metabolizes alcohol

by Jim DrydenNovember 26, 2018

Michael Worful

In the largest study of genetic factors linked to alcohol dependence, an international team of researchers identified a gene known to affect risk and determined that many other genes also contribute to risk for alcohol dependence to a lesser degree. In addition, the study linked genetic factors associated with alcohol dependence to other psychiatric disorders, such as depression, and showed that genetic factors tied to typical drinking sometimes are different from those linked to alcohol dependence.

The new analysis, from the Substance Use Disorders working group of the Psychiatric Genomics Consortium, adds to the current understanding of alcohol dependence, a complex disorder influenced by genes, environment and their interactions.

The gene that was conclusively associated with risk of alcohol dependence regulates how quickly the body metabolizes alcohol. The effects of other genes weren’t big enough to reach statistical significance individually — even though this study involved more than 50,000 people — but their combined effects were significant.

The goal of the research was to better understand how genes may contribute to alcohol problems as a way to develop improved and more personalized treatments.

The study is published online Nov. 26 in the journal Nature Neuroscience.

“The current estimate is that one in eight Americans suffers from alcohol dependence,” said senior author Arpana Agrawal, PhD, a professor of psychiatry at Washington University School of Medicine in St. Louis. “And the gene we identified has a protective effect, but by no means is it the only thing affecting risk of alcohol dependence. We know environmental factors also play a role. We also think the genetic susceptibility to alcohol dependence stems from the small, cumulative effects of a very large number of variants across the genome.”

The analysis compared genetic variants from nearly 15,000 individuals diagnosed with alcohol dependence to nearly 38,000 people without such a diagnosis.

To gather such a large sample, Agrawal — with colleagues from the Yale University School of Medicine, the Indiana University School of Medicine, the Broad Institute and other centers around the world —  analyzed data from 28 genetic studies of alcoholism in eight countries. But the researchers believe even larger studies will be needed in the future because genetic studies of other psychiatric disorders have required DNA from between 40,000 and 100,000 patients to allow researchers to isolate dozens of gene variants related to conditions such as schizophrenia and depression.

“As we analyze additional alcohol-dependent individuals, we should be able to find additional genomic regions affecting risk for alcohol dependence,” said first author Raymond Walters, of the Broad Institute of MIT and Harvard. “We know there are other DNA regions that have small effects on risk, but it’s going to take a large increase in our sample size before we can robustly identify those variants.”

The one gene that did stand out, called ADH1B, regulates how the body converts alcohol to a substance called acetaldehyde. Variants in the gene speed the conversion to acetaldehyde — a compound linked to unpleasant side effects from drinking — and that compound has a protective effect, making people less likely to drink heavily or become alcoholics. A current drug, disulfuram (Antabuse), works on the same metabolic processes as the gene variants identified in this study.

The researchers found that the genetic risk factors related to alcohol dependence also were linked to risk for other psychiatric disorders, such as depression, schizophrenia, ADHD and the use of cigarettes and marijuana. They plan to continue investigating those links between genetic susceptibility to alcohol dependence and risk for other types of psychiatric illness.

“There were genetic links both to other psychiatric disorders, such as depression, and to use of cigarettes and other drugs like cannabis,” said Joel Gelernter, MD, of Yale University. “As we study larger numbers of people, we expect to be able to determine at least to some extent how much of this correlation, or shared risk, is attributable to alcoholism, and how much may be the consequence of these other disorders.”

A key aspect of the new study is that it included genetic data from people of European (46,568) and African (6,280) ancestry. Although the same ADH1B gene was linked to alcoholism risk both in people of European ancestry and African ancestry, the researchers found that different variants in the gene altered risk in the two populations. Other research has revealed that the same variation in the same gene as occurs in Europeans also influences risk in people of Asian descent, but that data was not included in this study.

“There have been very large genetic studies of Europeans but not as much research in African populations to try to understand what genetic factors underlie risk for alcoholism,” said Howard J. Edenberg, PhD, of Indiana University. “In the future, we need to study much larger numbers of people from non-European populations because we don’t know as much about genetic factors that affect their risk. As our study showed, these factors can differ from population to population.”

The researchers also found that the genetic factors related to simply drinking alcohol were a little different from the genetic factors that contributed to alcohol dependence. In other words, at least at the genetic level, there’s a difference between simply drinking alcohol, even large amounts of alcohol, and becoming dependent on it.

“People suffering from alcohol dependence generally drink a great deal, but they also experience other problems related to their drinking, like losing control over when and how much they drink,” Agrawal explained. “I think it’s likely that as the sample sizes of our studies increase, we may find new DNA variants related to these problematic aspects of alcohol dependence but possibly not related to typical drinking.”

She said those larger samples of individuals with and without a diagnosis of alcohol dependence will be key to future discoveries about genetic contributions to alcoholism.

“The risk conferred by the ADH1B gene is one of the strongest single-gene effects seen in people with a psychiatric illness, but overall, it explains only a small proportion of the risk,” Agrawal said. “Many additional gene variants are making small contributions to alcoholism risk, but to find them, we’ll need to study more people.”

Walters RK et al. Trans-ancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders. Nature Neuroscience, published online Nov. 26, 2018.

This work was supported by the National Institute on Drug Abuse, the National Institute of Mental Health and previously was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (NIH). For a complete list of grant numbers, please refer to the paper. Additional funding from the Netherlands Scientific Organization, the Dutch Brain Foundation and the VU University Amsterdam. The authors also thank the 23and Me research participants and employees for making the study possible.

Potential conflicts of interest involving researchers who are authors of the study also are listed at the end of the paper. Some have received consultancy/speaking fees from various pharmaceutical companies and other business interests. Among faculty at Washington University School of Medicine, LJ Bierut, JP Rice and the spouse of NL Saccone are among the listed inventors on US Patent 8 080 371, “Markers for Addiction,” covering the use of certain DNA SNPs in determining the diagnosis, prognosis and treatment of addiction.

Washington University School of Medicine’s 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.