The results of new research headed by a team at Washington University School of Medicine in St. Louis suggest that a common genetic signature may increase an individual’s risk of developing substance use disorders (SUDs), regardless of whether the addiction is to alcohol, tobacco, cannabis, or opioids. The researchers carried out a multivariate genome-wide association meta-analysis of the largest genome-wide association studies (GWAS) of SUDs, which together included genomic data from more than 1.1 million people of mostly European ancestry and a smaller population of people of African ancestry.
In addition to identifying genetic loci that were linked with addiction to specific substances—alcohol, tobacco, cannabis, and opioids—the results identified more than a dozen independent single-nucleotide polymorphisms (SNPs) that were genome-wide significant for the general addiction risk factor (addiction-rf). The findings, the team suggested, could eventually lead to universal therapies for multiple substance use disorders, including treatments for treating more than one SUD in the same individual.
“There is a tremendous need for treatments that target addiction generally, given patterns of the use of multiple substances, lifetime substance use, and severity seen in the clinic,” said Alexander Hatoum, PhD, a research assistant professor of psychological & brain sciences at Washington University. “Our study opens the door to identifying medications that may be leveraged to treat addiction broadly, which may be especially useful for treating more severe forms, including addiction to multiple substances.” Hatoum is co-senior author of the researcher’s published paper in Nature Mental Health, which is titled “Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders.” In their report, the authors concluded, “These findings provide insight into genetic risk loci for substance use disorders that could be leveraged as treatment targets.”
The incidence of SUDs has increased dramatically in recent years, with rising numbers of overdose deaths and increasing social, emotional, and financial costs to families and communities. More than 46 million people over the age of 12 years in the United States had at least one SUD in 2021, according to the National Survey on Drug Use and Health. And as the authors further noted, “… in the United States, 13.5% of deaths among young adults are attributable to alcohol, smoking is the leading risk factor for mortality in males, and the odds of dying by opioid overdose are greater than those of dying in a motor vehicle crash.” However, they continued, “Despite the large impact of substance use and substance use disorders, there is limited knowledge of the molecular genetic underpinnings of addiction broadly.” And while the most severe cases of SUD typically involve the use of more than one substance, most medications target the use of a specific substance, such as tobacco or opioids, rather than treating addiction broadly.
The risk of developing SUDs is influenced by the complex interplay of genetics and environment. But recent large-scale genome-wide association studies suggest that the genetic architecture of SUDs is characterized by a high degree of commonality, “that is, a general addiction genetic factor likely conveys vulnerability to multiple SUDs,” the team wrote.
For their newly reported study, Hatoum and colleagues carried out a multivariate genome-wide association meta-analysis of the largest discovery GWAS of SUDs, spanning problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD). This type of genome-wide association study can identify key genetic variations that are associated with increased risk of having one or multiple disorders. The analysis included data from 1,025,550 people of European ancestry and 92,630 people of African ancestry.
The results identified 19 SNPs that were significantly associated with general addiction risk, and which could potentially inform future development of universal therapies for multiple addictions. The study findings also discovered 47 genetic variants that were linked to specific substance disorders; nine for alcohol, 32 for tobacco, five for cannabis, and one for opioids. These findings could feasibly help inform novel treatments for addiction to individual substances. It is also likely that many more genetic differences are involved in shaping a person’s genetic liability to one or more addictions.
Co-senior authors on the study included Arpana Agrawal, PhD, a professor of psychiatry at Washington University School of Medicine; Ryan Bogdan, PhD, a professor of psychological & brain sciences at Washington University; Howard J. Edenberg, PhD, of Indiana University School of Medicine; and Joel Gelernter, MD, of the Yale School of Medicine. More than 150 researchers from institutions around the world were involved, with NIH funding for the study coming from the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Mental Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Aging.
“This study represents a major advance in understanding how genetic factors predispose people to substance use disorders,” Agrawal said. “While we have known for a while that many genetic factors are shared between different substance use disorders, our study identified some of the contributing genes, providing avenues for future biological and therapeutic discoveries for individuals with multiple addictions.”
The identified genetic signature associated with SUDs encompasses variations in multiple genes, and is linked to regulation of dopamine signaling. Dopamine is a key signaling molecule in the brain’s reward system. Studies have shown that repeated exposures to addictive substances can cause the dopamine pathway in the brain to adapt to the effects of these substances, requiring more of the substance in order to receive the same amount of reward. But while prior research has implicated dopamine signaling in addiction, most studies have focused on a single substance. Further, the regulation of dopamine and neuronal development from the newly discovered genetic signature could potentially help home in on the specific forms of neuronal communication that are affected in SUDs.
“Our analyses suggest that the regulation or modulation of dopaminergic genes, rather than variation in dopaminergic genes themselves, is central to general addiction liability,” they wrote. DRD2—which plays a role in reward sensitivity and may also be central to executive functioning—was “the top gene signal, which was mapped via chromatin refolding, suggesting a regulatory mechanism, the authors noted. Other regulatory effects on dopaminergic pathways were supported by the signal at PDE4B. This gene has previously been implicated in disinhibition traits, while the phosphodiesterase (PDE) system has been proposed as a dopaminergic regulation mechanism, the team noted. “… animal studies suggest that the PDE system is associated with downregulation of drug-seeking behaviors across opioids, alcohol, and psychostimulants … Notably, the PDE4B antagonist, ibudilast, has been shown to reduce heavy drinking among patients with AUD and also shown to reduce inflammation in methamphetamine use disorder …”.
“Anytime we look at addiction, we think dopamine is involved,” Hatoum said. “But here, we can implicate more specific mechanisms by which the brain regulates response to dopamine across different substances, and ultimately find processes that could reverse maladaptive regulation that leads to addiction.”
Separately, genomic analysis of individuals of African ancestry showed only one genetic variation associated with general addiction risk and one substance-specific variation for risk of alcohol use disorder. The smaller sample size may be one reason for the more limited findings in this population. Hatoum emphasized the need for data collection on SUDs in even larger and more diverse ancestral populations to tease apart whether these associations are universal or vary across ancestries.
Interestingly. the addiction-rf polygenic risk score (PRS) was associated with an increased likelihood of developing other health problems, including bipolar disorder, suicidal behavior, respiratory disease, heart disease, and chronic pain. “The addiction-rf PRS was associated with many medical conditions characterized by high morbidity and mortality rates, including psychiatric illnesses, self-harming behaviors, and somatic diseases that could be consequences of chronic substance use (for example, chronic airway obstruction) or precursors to heavy substance use (for example, chronic pain).”
Interestingly, the team noted, the addiction-rf PRS was more strongly linked with the use of drugs to cope with internalizing disorder symptoms (anxiety and depression), than with the psychiatric traits and disorders per se. This, they continued, suggests that “genetic correlation between SUDs and mood disorders may partially be attributable to a predisposition to use substances to alleviate negative mood states (‘self-medication’).”
To serve as a control group for exposure to addictive substances, genetic data from 4,491 nine- and 10-year-old children of European ancestry who are participating in the national Adolescent Brain Cognitive Development Study—and who had not yet used addictive substances—were also analyzed. The researchers found that children with the genetic signature for addiction were more likely to be related to someone who has a substance use disorder. The children also were more likely to show impulsive personality traits and disrupted sleep patterns, highlighting the possible role of these genes in early life behaviors, even before substance use occurs. “… in a sample of drug-naive children, the addiction-rf PRS was correlated with parental substance use problems and externalizing behavior,” the researchers stated.
“This study could ultimately shift our conceptualization of addictive disorders, allowing novel pathways to research that will uncover more effective therapies for addiction,” Hatoum said. As part of the study, the researchers compiled a list of approved and investigational drugs that have the potential to be repurposed to treat SUDs because they target the effects of the newly discovered addiction genetic signature. The list includes more than 100 drugs to investigate in future clinical trials, including those that can influence regulation of dopamine signaling. This drug repurposing analysis, the investigators wrote, “identified 104 medications approved by the U.S. Food and Drug Administration (FDA) that reverse the addiction-rf transcriptional profile.” Among those identified were medications currently used to treat SUDs (for example, varenicline for smoking cessation), other psychiatric conditions—for example, reboxetine for depression— as well as drugs currently used for other indications, including mifepristone, which is used for pregnancy termination and is currently under clinical investigation for treating AUD, and riluzole, which is a treatment for amyotrophic lateral sclerosis.
