In recent years, studies involving large numbers of individuals have identified numerous locations in the human genome where commonly occurring variations in DNA sequence are associated with significantly increased risk for specific disorders involving the use of alcohol, nicotine, cannabis, and opioids.

Now, an international team of over 150 researchers, including many who have been supported by BBRF grants, has reported the identification of 19 DNA variants that are commonly inherited by individuals across these four substance-use disorders, irrespective of the specific substance used. The team describes this signal from the genome as a “general addiction risk factor,” and notes that it likely applies to addiction to substances in addition to those at the focus of their study.

The team was led by Alexander S. Hatoum, Ph.D., of Washington University, St. Louis. Members of the team included Sandra Sanchez-Roige, Ph.D., a 2018 BBRF Young Investigator, Renato Polimanti, Ph.D., a 2015 BBRF Young Investigator, Alexis Edwards, Ph.D., a 2016 BBRF Young Investigator, and Emma C. Johnson, Ph.D., a 2020 BBRF Young Investigator. Many other BBRF grantees were involved in the project through their participation in the Substance Use Disorder Working Group of the Psychiatric Genomics Consortium. The team’s results were published in Nature Mental Health.

The study, based upon a meta-analysis (a study of past studies) involving over 1 million individuals of European ancestry and over 92,000 of African ancestry, also succeeded in identifying genome variations specific for risk of disorders involving use of alcohol (9), tobacco (32), cannabis (5), and opioids (1).

In 2021, according to the National Institutes of Health, over 46 million Americans age 12 and older had at least one substance-use disorder, of whom only 6.3% received treatment. In the same year, an estimated 107,000 Americans died of drug overdoses. While substance-use disorders are known to be heritable, they are also known to be influenced by complex interactions among multiple genes and environmental factors.

The advent of genome-wide association studies (sometimes called “GWAS” studies) has enabled researchers to begin to understand where to look in the genome for vulnerabilities, which in turn provide potential insights for future treatments.

Some of these insights are obtained by considering the biological functions associated with genes and genomic locations that have been linked in GWAS studies with heightened substance-use risk. In the newly published finding of a general addiction risk factor in the genome, the researchers found that variations in several genes affecting the regulation of the neurotransmitter dopamine are linked with cross-substance vulnerability in those who carry these variations.

Past research has identified the role of dopamine in the brain’s striatum as being central in positive drug reinforcement. The gene encoding the DRD2 dopamine receptor, in addition, has been found to play a role in reward sensitivity and may also be important in the brain’s executive function, the researchers wrote. “The interplay of reward and cognition is likely relevant throughout the course of addiction,” they noted. Their findings, they said, “reinforce the role of dopamine signaling in addiction.”

Regarding the substance-specific genetic signals they found, the team said they fell into three broad categories: genes having a role in drug-specific metabolism, drug receptors in nerve cells, and general neurotransmitter mechanisms.

The analysis also highlighted “the robust genetic association” of the general addiction risk factor “with serious mental and bodily illnesses.” One interesting finding was that the general addiction risk signal was more strongly associated with using drugs to cope with problems such as anxiety or depression than with those disorders themselves. The analysis “suggests that correlations between substance-use disorders and mood disorders may partially be attributable to a [genetic] predisposition to use substances to alleviate negative mood states i.e., self-medication,” the team wrote.

“Substance-use disorders and mental disorders often co-occur, and we know that the most effective treatments help people address both issues at the same time,” said Joshua A. Gordon M.D., Ph.D., the Director of the National Institutes of Mental Health and a two-time BBRF grantee and member of BBRF’s Scientific Council. “The shared mechanisms between substance use and mental disorders revealed in this study underscore the importance of thinking about these disorders in tandem.”

One of the next steps in the genomic study of substance-use risk, the team said, was to include much larger and more diverse study populations in the analytical cohort. The African ancestry component of the current study was about 9 percent of the size of the European cohort, and may have been too small to detect robust genomic risk signals specific to that population. Additional populations from across the globe should be part of future studies, Dr. Hartoun said.

Nora Volkow, M.D., Director of the National Institute on Drug Abuse, and a BBRF Scientific Council member, commented: “A better understanding of genetics brings us one step closer to developing personalized interventions that are tailored to an individual’s unique biology, environment and lived experience in order to provide the most benefits.”