Most of the genetic risk for developing a substance use disorder comes from genes that broadly affect how the brain processes rewards, regulates impulses, and weighs consequences, according to a Rutgers Health–led study published on Mar. 22. The research was led by Holly Poore, faculty instructor of psychiatry at Rutgers Robert Wood Johnson Medical School, and analyzed genetic data from more than 2.2 million individuals.
The findings are significant because they suggest that vulnerability to alcohol, tobacco, cannabis, and opioid use disorders is shaped more by general genetic factors related to behavior than by genes specific to any single drug. This could influence future prevention and treatment strategies for addiction.
Researchers used advanced genomic methods to analyze four substance use disorders alongside related traits such as attention deficit hyperactivity disorder (ADHD), risk-taking behaviors, and initiation of substance use. This approach allowed them to identify hundreds of genetic variants associated with both broad externalizing liability and substance-specific risks. "Those same genes show up across many outcomes – things like ADHD, conduct problems and other risky behaviors – and then layered on top of that are genes that are more specific to each substance. What this paper does, for the first time, is tease apart those pathways at the genomic level," Dick said.
The study found that modeling addiction together with these other traits increased the ability to detect genetic effects without losing sight of signals unique to each substance. Many broad-risk genes were involved in brain signaling and reward processing, while substance-specific genes mapped onto pathways such as alcohol metabolism or receptors implicated in tobacco use. "Traditionally, gene-finding efforts have focused on one disorder at a time," Poore said. "But substance use disorders almost never occur in isolation... By modeling that shared genetic architecture directly, we were able to discover more about both the broad and specific biological pathways that contribute to addiction."
Researchers also developed polygenic scores—summary measures combining thousands of genetic variants—to predict risk for multiple or specific substance use disorders. Dick said: "A broader metric can tell us who is generally more vulnerable to addiction... while more specific scores can help us understand who is at higher risk for problems with different substances... Genetic risk scores may also help us develop more individualized treatments and recovery plans." Network analyses pointed toward potential biological systems and medications for treatment.
The authors noted their analyses were limited to individuals of European ancestry due to available datasets but emphasized the need for diverse genomic research moving forward. "Addiction is incredibly complex, and this study shows just how important it is to look beyond any single substance or single gene," Poore said. "By understanding the common genetic roots... we can build a more complete picture of vulnerability and ultimately support better prevention, intervention and treatment strategies."
