By Dr. Mark Gold
New Yale Study Found 29 Genetic Risk Factors
Psychiatric disorders are among the most common and most commonly ignored illnesses in the world. They affect more than 25% of the population in any given year and are a leading cause of worldwide disability. Genes influence the risk of psychiatric disorders. The importance of genetics has been established by twin studies, where identical twins separated at birth and reared apart are remarkably similar, and, more recently, large-scale genomic studies. This is not a case of exception to the rule. Most psychiatric disorders are highly heritable; the estimated heritability for bipolar disorder or schizophrenia is much higher than that of diseases like breast cancer and Parkinson’s disease.
Genes are one part of the puzzle, but an important part. Psychiatric disorders are highly polygenic.1 Alcohol use and substance use disorders are less well understood. Genetic factors underlying addiction are an important part of the disease’s development. They can also be hard to figure out, leaving patients to puzzle over their family history or search through complicated records as they try to understand their own risks. We sometimes see variables affecting our health through a glass darkly, and the mysteries aren’t affirming or reassuring or helpful. This can be especially true of individual risk for conditions like alcohol use disorder (AUD), as family and cultural narratives about AUD often extend back generations.
So it’s a hopeful sign when researchers learn more about genetic influences on SUD, and what we learn can guide later innovations in treatment and prevention. An international team of researchers, including Hang Zhou from the Department of Psychiatry, Yale School of Medicine, and colleagues, recently found 29 genetic influences on problematic alcohol use, and linked some of them to other individual traits, like mental health conditions.2 This helped the team measure shared genetic vulnerabilities for different issues, an important step for identifying individual risks. They published their findings in Nature Neuroscience in May.
What did this study find about genetic risks and alcohol use?
Zhou et al. first collected genetic information stored in different databases. This stored information came from over 435,000 people of European ancestry. Data on other ancestry groups is largely lacking—this research team notes that African-Americans make up the largest non-European study group for genetic influences on alcohol, but considerably more work will have to be put into identifying African-ancestry data and information from other non-European groups to achieve viable study results. Zhou et al. then compared their collected genetic information to data on alcohol use and other lifestyle factors to measure which genetic factors were associated with problematic alcohol use, a broadly inclusive term the team used to cover AUD and “physiological dependence and/or significant psychological, social or medical consequences.” Zhou et al. cross-referenced their identified genetic risk factors with tendencies in the general population to isolate influence on problematic use.
They found 29 genetic risk factors for problematic alcohol use, of which 10 had been previously spotted and 19 were new. They also had information on genetic risk factors for other health correlates and mental health issues and were able to compare which genetic influences matched for different risks. Schizophrenia was correlated with problematic alcohol use, along with other mood disorders and substance use disorders. The team also detected links between problematic use and number of sexual partners, worry, and smoking. Education level and cognitive performance “showed protective effects on liability to AUD.” Zhou et al. analyzed how different genetic risk factors influenced each other here, giving them a sense of the ways in which different traits may interact with problematic use. As a result, they could find connections between problem drinking and mental health conditions like anxiety and depression, helping to confirm results from other studies and expert understandings of AUD and problematic use.
Why is this important?
Yale’s Joel Gelernter, the senior author in the study, said that “The new data triple the number of known genetic risk loci associated with problematic alcohol use.” These results confirm prior identifications of genetic risk factors for AUD and problem drinking while finding a host of new influences, important documentation that allows researchers to understand more fully traits underlying individual trajectories with alcohol use.
AUD is a complex condition or conditions and there is no single cause of its development, which often varies dramatically over time and in different circumstances and even cultures, but this study helps us recognize that there is an important genetic component shaping individual risk. The findings should help researchers and practitioners more effectively gauge individual risk for AUD and problem drinking. Over time, they could also help us develop targeted treatments—treatments tailored for individuals and for specific genetic risk factors they may have.
The authors also recognize limitations in their work, including its reliance on European ancestry. It is valuable to keep these limitations—and the larger mix of social, political, economic, and cultural factors that affect any given person’s likelihood of developing an AUD or problematic drinking—in mind when considering genetic influences, but it’s also important not to overlook underlying traits that can cause significant problems in our lives. It’s generally true of substance use that we all carry different levels of risk; being mindful of them is helpful for the choices we make and the outcomes we should monitor. Opioid use disorder (OUD) appears to be linked to multiple traits, including psychiatric conditions, neuroticism, depression, and substance use.3 AUDs are likely to be complicated by co-occuring conditions, life experiences, trauma, early drinking, and associations with other traits.
Genes act by producing specific proteins that may contribute to a particular biological or behavioral trait. So while this study is very important, identifying genes that may play a role in any complex disease is only a first step in understanding how a gene or genes affect an individual. Each of us have 80,000-100,000 genes that shape who we are; learning about them should enhance treatment and prevention for many diseases.
Genetic studies of SUDs and psychiatric illnesses are advancing rapidly. But these research advances do not, by themselves, help patients. Ultimately , as Harvard University’s Dr. Steve Hyman once said, “...genetic research helps no one if all we end up with are gene lists.” AUD often seems to run in families, and we may hear many patients talk about their parents, grandparents, and family members having problems with alcohol and going to treatment for AUD. Popular media also focuses on stories about scientific studies of a gene explaining AUD. Genetics influence the odds of developing AUD, but it is complicated. Putting all of the research together leads to the conclusion that genes are responsible for about half of the risk for AUD. Multiple genes, like those studied and reported by the Yale group, play a role in a person’s risk for developing AUD.
Neurobiological research progress can utilize genetic information to move beyond the DSM toward more logical disease groups based on biology. Genetic research progress can help us find new therapeutics based on this knowledge. Genetic research progress like that reported by the Gelertner laboratory at Yale helps everyone understand that addiction is a complex and multifactorial-determined disease. AUD Genetic knowledge helps to destigmatize and remove harsh associations of SUD with individual weakness, indiscipline, and deficient virtue, and spur advancements in life-altering and life-saving medications and interventions. That’s a pretty good day’s work for a study.
Lee, P.H., et al. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders. Cell, 2019; 179 (7): 1469 DOI: 10.1016/j.cell.2019.11.020
Zhou, H., Sealock, J. M., Sanchez-Roige, S., et al. (2020). Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits. Nature Neuroscience. https://doi.org/10.1038/s41593-020-0643-5
Zhou, H., Rentsch, C. T., Cheng, Z., Kember, et al. (2020). Association of OPRM1 Functional Coding Variant With Opioid Use Disorder. JAMA Psychiatry, E1–E9. https://doi.org/10.1001/jamapsychiatry.2020.1206
Dr. Mark S. Gold is a teacher of the year, translational researcher, author, mentor and inventor best known for his work on the brain systems underlying the effects of opiate drugs, cocaine and food.