Guest Blog: Genetics and Addiction: What We’ve Learned

Are you mostly a product of the genes you inherit or your experiences in life? This question intrigues many people, including addiction researchers. In this post, I provide an overview of key research on the genetic inheritance of substance use disorders such as alcohol use disorder, opioid use disorder, and cannabis/marijuana use disorder.

Some researchers, such as at the Washington University School of Medicine in St. Louis, seek to identify genes common to addictive disorders based on information from the DNA code of more than a million people. So far, these researchers have identified 47 genetic variants linked to substance disorders, including 32 for tobacco, 9 for alcohol, 5 for cannabis, and one for opioid addiction.

Alcohol use disorder (AUD) has been studied for years, starting with twin studies comparing identical or fraternal twins and their risk for AUD and adoption studies comparing adopted children to their birth parents. These studies demonstrated that the heritability of alcohol dependence is up to 60%. Some genes increase a person’s risk for AUD, while others decrease that risk directly or indirectly. For instance, some people of Asian descent carry a gene variant altering their rate of alcohol metabolism, causing symptoms like flushing, nausea, and rapid heartbeat when they drink even a little alcohol. These genes may help protect them from developing AUD.

Twenty-two percent of adults in the United States have at least one biological parent with alcohol use disorder (AUD). The odds of lifetime AUD are 2.5 times higher for the offspring of one AUD parent and 4.4 times higher for the offspring of two AUD parents, as compared to children of non-AUD parents.

Genes are not destiny, and environmental experiences also play a role. For example, a study of more than 3 million people suggests that marriage may protect against AUD, particularly for those with genetic loading for AUD. However, researchers also noted that while marriage to a spouse without alcohol problems may protect against alcohol use disorders, being married to a spouse with alcohol use problems has the opposite effect, increasing one’s risk.

It is also known that pain, either psychological or physical, as well as PTSD and trauma, can make AUD more likely, as the additive relief of distress seems to increase brain-related rewards derived from alcohol.

Currently, treatment of AUD is limited to only several FDA-approved and a few non-approved drugs which often have only modest effects in inhibiting drinking, largely because they work well only for certain individuals. But thanks to new research, we now know which individuals are most likely to respond significantly better to one often-used AUD treatment: naltrexone.

Raymond Anton, Jr., MD is an international expert on alcohol use disorder, an addiction psychiatrist, and clinical neuroscientist, as well as researcher of genetic variants predicting treatment-response to AUD medications such as naltrexone. He and his colleagues discovered that it was not one gene, but rather a combination of genes known to affect key brain chemicals impacted by alcohol that made a difference in whether naltrexone was effective in people with AUD. For example, in two different studies, they found that a gene variation known to impact the brain opiate receptor gene, combined with variations in two genes thought to control brain dopamine, influenced how well naltrexone worked in reducing/controlling drinking in individuals with AUD. The first study evaluated genes inherited from one’s parents (germ line mutations) and the second evaluated epigenetic markers (likely acquired over a lifetime). Epigenetic markers refer to changes to gene functioning occurring in life secondary to behavior (such as drinking alcohol) or various outside influences such as other diseases, stress, etc.

The specific mechanism that drives opioid death by overdose is stimulation of one class of endogenous opioid receptors—mu-opioid receptors—in cells in the brainstem; it inhibits breathing. Respiratory depression, or decreased (or terminated) breathing, is a direct effect of opioid use, and, in the case of fentanyl, it appears extremely quickly.

Intravenous naloxone is not available in the community, where first responders depend on intranasal or intramuscular administration. Yet naloxone must be administered much sooner for fentanyl than for heroin because the window for saving the overdosed person is much shorter than with heroin. So, the right dose of naloxone must be given by a friend, loved one, or first responder almost immediately.

Other opioid antagonists, like nalmefene, may be expected to do a better job in fentanyl overdoses. After the person recovers, they should be offered long-term treatment resources, including the ability to initiate treatment for opioid use disorder in the emergency department, as Yale’s Brian Fuerhlein described in an earlier blog post.

As a result of Anton’s research, it’s clear that personalized treatment and choosing the right medication for the right patient is becoming possible in AUD. For example, performing a few relatively simple genetic tests identifying variations in three brain genes will enable physicians to predict which patients would benefit most from taking naltrexone, an FDA-approved medication for AUD. If tests show patients will not benefit, other medications could be tried. Alternatively, new medications might be developed based on genetic testing results. Rather than taking a drug that could never work well because of one’s genetic makeup, wouldn’t it be best to know this upfront and potentially choose an alternative? Also, knowing a drug is likely to work might encourage more people to consider medication-assisted treatment.

Early life experiences, such as childhood trauma, parental alcohol use, and exposure to alcohol during critical periods of brain development, may have lasting effects on neurobiological systems involved in addiction. These environmental influences may interact with genetic predispositions, shaping an individual’s vulnerability to AUD. Early alcohol or drug experimentation; physical, sexual, or emotional trauma; and other risk factors, such as second- or third-hand smoke exposure, abusive parenting, parental substance use, and other factors also play a role.

Sometimes, the environment plays a key role in the development of a disorder. The findings in one study showed that environmental factors explained more of the risk for opioid dependence than polygenic risk scores—a number estimating how genetic variants affect an individual’s risk of developing a disease. Polygenic risk scores combine different versions of many genes related to a specific disease. The researchers found selected environmental factors, such as annual household income and education level, explained an average three-fold greater risk for opioid use disorder (OUD) compared with opioid use disorder polygenic risk scores alone.

But don’t count out genetics. Although researchers found environmental factors played a larger role, opioid polygenic risk scores explained 8% of the variance of the risk for opioid dependence. The study also found that among people with higher polygenic risk scores, individuals with a higher education level were less likely to have opioid dependence, whereas those with posttraumatic stress disorder (PTSD) were more likely to have opioid dependence.

A new study by Yale School of Medicine researchers assessed how genetic and psychosocial predictors of opioid use disorder are predictive for a person becoming dependent on opioids. In the VA and Yale study, researchers analyzed genetic data from nearly 2,000 people who participated in a prior study by Yale and University of Pennsylvania researchers (called the Yale-Penn study) on substance use genetics. Researchers examined the role of recently developed polygenic risk scores for opioid use disorder and environmental factors such as education level, adverse childhood experiences, and psychiatric conditions. “We’ve made great progress in understanding some of the genetic and environmental factors that influence risk for opioid use disorder, but we know less about the complex interplay between them,” said Yale’s Joseph Deak.

Marijuana is the most commonly used federally illegal drug in the United States, with half of all Americans saying they have tried it at some time. Experts estimate that among people who use cannabis, up to 30% may have marijuana use disorder (which is the same as cannabis use disorder, or CUD). The risk of developing cannabis use disorder is greater in people who start using marijuana during youth or adolescence and who use marijuana more frequently.

It has been estimated that 50%-70% of an individual’s risk for cannabis use disorder is due to genetic factors, although environmental factors also play a role. Yale’s group, led by Joel Gelertner, has been trying to identify these risks and predict who might develop cannabis use disorder, with its many negative outcomes, including increased risk of psychiatric disorders, heart disease, cancer, and respiratory illnesses.

Researchers examined a genome-wide set of genetic variants in individuals from multiple ancestry groups enrolled in the U.S. Department of Veterans Affairs’ Million Veteran Program, one of the world’s largest genetic databases. They identified dozens of genetic variants linked to cannabis use disorder and a variety of behavioral and health issues associated with CUD.

The findings offer insights into genetic factors and potentially related health risks. For instance, researchers found that variants of genes encoding for three different types of receptors on neurons were associated with an elevated risk for developing CUD. In addition, variants linked to CUD were associated with the development of lung cancer. The authors noted that more work needs to be done to separate the effects of tobacco use and other environmental factors on cancer diagnoses from those of marijuana use.

Genetics researchers have leveraged new CUD genomics data to complete a genetically-informed analysis with unprecedented power, which showed causal relationships between CUD and with risk for developing SUDs in April 2024. This new finding is the strongest evidence to date that cannabis use disorder and even cannabis use significantly increases the risk for other substance use disorders.