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Genetic Risk of Substance Use Disorders Untangled in Large-Scale GWAS Meta-Analysis

NEW YORK – An international research consortium led by scientists at Washington University in St. Louis has uncovered genetic risk loci associated with many forms of addiction, including to alcohol, tobacco, opioids, and cannabis.

The results, from a large-scale genome-wide association study meta-analysis that comprised more than 1.1 million individuals, hinted at genetic overlap between substance abuse and mental disorders and pointed to possible new treatments. "Using genomics, we can create a data-driven pipeline to prioritize existing medications for further study and improve chances of discovering new treatments," Alexander Hatoum, lead author of the study and a research assistant professor of psychological and brain sciences at WashU, said in a statement.

According to the US National Institutes of Health, more than 46 million people in the US aged 12 or older had at least one substance use disorder in 2021, and only 6.3 percent received treatment. Approximately 107,000 people died of drug overdoses that year, and 37 percent of the deaths involved simultaneous exposure to both opioids and stimulant drugs.

For their study, sponsored by the NIH and published in Nature Mental Health on Wednesday, the researchers analyzed genomic data from 1,025,550 people of European descent and 92,630 individuals of African ancestry.

Among the European samples, they found 19 SNPs associated with general addiction risk. "There is a molecular pattern of association that is related to addiction regardless of the substance," Hatoum told GenomeWeb.

"Clinics tend to treat for a particular substance but don't [consider] substance use disorder risk factors that underlie all of these different substances," he added. According to Hatoum, the findings reiterate the need for treatments for all forms of addiction.

The consortium also found 47 SNPs that were associated with specific substance disorders such as alcohol use disorder, nicotine dependence, cannabis use disorder, and opioid use disorder in the European population. For the African ancestry samples, the researchers found just one SNP associated with general addiction risk and another one linked to risk of alcohol use disorder.

The study implicated genes such as PDE4B that are involved in the regulation of dopamine signaling across all substance addictions, bolstering previous studies that had also found links to dopamine regulation.

Another important result was that genetic variants associated with substance addition were good predictors of other conditions such as suicidal behavior, respiratory disease, heart disease, and chronic pain conditions.

"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. The shared genetic mechanisms between substance use and mental disorders revealed in this study underscore the importance of thinking about these disorders in tandem," said Joshua Gordon, director of the National Institute of Mental Health, in a statement.

Following a transcriptome-wide association study in brain samples from the Genotype-Tissue Expression (GTEx) resource and an analysis of the data with that from the Library of Integrated Network-Based Cellular Signatures (LINCS) database, the researchers identified 104 medications approved by the US Food and Drug Administration that reverse the addiction risk factor transcriptional profile and could be considered for drug repurposing.

Hatoum said he was excited about two drugs which they found in their drug repurposing study- methamphetamine and ibudilast which are at different stages of clinical trials.

Highlighting the limitations of the study, the researchers wrote that the low number of discoveries in the African-ancestry population could be due its small size, underscoring the need for data collection on substance use disorders in globally representative populations. "Right now, we are only capturing kind of the tip of the iceberg," Hatoum said.