The greatest genetic risk for developing a substance use disorder comes from genes that broadly affect how our brains process rewards, regulate impulses, and weigh consequences—not from genes that specifically affect substance use disorder or any single drug.
Researchers in a Rutgers Health study led by Holly Poore, professor of psychiatry at Rutgers Robert Wood Johnson Medical School, analyzed genetic data from previously published genome-wide association studies of more than 2.2 million people to understand how genes shape vulnerability to alcohol, tobacco, cannabis and opioid use disorders.
According to the study published in Nature Mental Health, The team members found that genetic risk works in two main pathways:
- A broad “behavioral mission” or externalizing pathway, which includes brain systems for reward processing, self-control, and risk-taking. Externalizing refers to an inherited pattern of behaviors characterized by difficulty regulating impulses and actions such as impulsivity, attention-deficit/hyperactivity disorder (ADHD), conduct problems, and risk-taking behaviors. This pathway crosses many forms of addiction and related behavioral outcomes.
- Substance-specific pathways that are more closely associated with specific drugs (for example, genes involved in alcohol metabolism or nicotinic receptors).
Most of the genetic predisposition to substance use disorders is not about how bodies respond to drugs. it’s about how brains are wired. Specifically, risk is mostly associated with genes that broadly influence the way our brains process rewards and regulate behavior.”
Danielle Dick, director of the Rutgers Addiction Research Center at the Rutgers Brain Health Institute and senior author of the study
Dick added, “These same genes show up in many outcomes—things like ADHD, conduct problems, and other risky behaviors—and then put genes that are more specific to each substance. What this paper does, for the first time, is separate those pathways at the genomic level.”
Using advanced genomic methods, the researchers analyzed four substance use disorders—alcohol, tobacco, cannabis, and opioids—along with associated externalizing traits such as ADHD, risk-taking, and substance use initiation. This approach allowed them to identify hundreds of genetic variants associated with a broad externalizing liability as well as genes that were more specific to certain substances.
The researchers found that modeling addiction along with these other traits greatly increased their ability to detect genetic effects without sacrificing the means to see substance-specific signals. Many of the genes associated with broad liability are involved in brain signaling, reward processing and neural plasticity, while substance-specific genes map to pathways such as alcohol metabolism or nicotinic acetylcholine receptors involved in tobacco use.
“Traditionally, gene-finding efforts have focused on one disorder at a time,” Poore said, noting how one genome-wide association study is on alcohol, another on tobacco, and so on. both broad and specific biological pathways that contribute to addiction’.
Researchers also used these genomic discoveries to create polygenic scores, summary measures that combine thousands of genetic variants into a single index of genetic liability. Broad polygenic externalizing scores were particularly powerful in predicting risk for multiple substance use disorders, whereas substance-specific scores provided more precise information about vulnerability to specific drugs, such as alcohol or nicotine.
“From a translational perspective, we can begin to think about genetic risk at two levels,” Dick said. “A broader measurement can tell us who is generally more vulnerable to addiction and other externalizing problems, while more specific scores can help us understand who is at greater risk for problems with different substances. This doesn’t mean that genes determine someone’s fate, but they can help us identify who might benefit most from targeted prevention or earlier intervention.”
In addition to mapping genetic risk pathways, the researchers conducted network and drug target analyzes that indicated potential biological systems and drugs that could be exploited or repurposed for treatment. Many of the genes identified for the broad externalizing pathway overlapped with those involved in other psychiatric and substance-related disorders, highlighting shared biology between the conditions.
The authors said their analyzes were limited to people of European descent, reflecting the current availability of large-scale genetic datasets and highlighting the urgent need for more diverse genomic research to ensure findings are relevant and equitable across populations.
“Addiction is incredibly complex, and this study shows how important it is to look beyond any single substance or gene,” Poore said. “By understanding the common genetic roots that link substance use disorders to other forms of behavioral inhibition – as well as the pathways specific to alcohol, nicotine, cannabis or opioids – we can build a more comprehensive picture of vulnerability and ultimately support better prevention, intervention and treatment strategies.”
The study was authored by an international team of researchers from SUNY Downstate Health Sciences University, University of California San Diego, Massachusetts General Hospital and Harvard Medical School, Washington University School of Medicine, Emory University, University of Texas at Austin, Vanderbilt University Medical Center and collaborators from the Collaborative Study on the Genetics of Alco, among others.
