Substance use disorders (SUDs) are mental health conditions characterized by the compulsive, uncontrolled and deleterious use of alcohol, tobacco, stimulants (e.g., cocaine or methamphetamines), opioids, cannabis and/or various other substances. These disorders are a key health concern worldwide, as they can be highly debilitating and can sometimes even lead to serious diseases, physical disabilities and even death.

While several studies have tried to uncover the factors that increase the risk of developing SUDs, much about their origin remains poorly understood. Past findings suggest that these disorders have a genetic component and are often accompanied by other psychiatric conditions or psychopathological symptoms, such as depression and anxiety.

Researchers at Indiana University School of Medicine and other institutes recently set out to shed further light on the genetic variants (i.e., differences in people’s DNA sequence) that are linked to a greater risk of developing SUDs, by analyzing the results of multiple earlier genetic studies. Their paper, published in Molecular Psychiatry, pinpoints 220 genetic loci (i.e., specific locations of a gene or DNA segment on a chromosome) linked to the emergence of SUDs, 40 of which were never identified before.

“SUDs (including alcohol, cannabis, opioids, and tobacco) represent significant public health challenges,” wrote Dongbing Lai, Michael Zhang and their colleagues in their paper. “The estimated heritability of SUDs is ~50% and many individuals experience multiple SUDs concurrently. Studies have demonstrated the existence of genes shared across multiple SUDs, and identifying these SUD-shared genes is critical to developing novel prevention and treatment strategies.

“We conducted the largest cross SUD meta-analysis to date to identify SUD-shared genes using samples genetically similar to 1000 Genomes Project European (1kg-EUR-like), African (1kg-AFR-like), and American mixed (1kg-AMR-like) populations.”

Lai, Zhang and his colleagues analyzed data collected as part of earlier studies involving African, American and European populations using computational techniques. This allowed them to identify 785 genes that were associated with several SUDs.

The researchers subsequently tried to determine whether these genes were active in specific brain regions. In addition, they used the results of their analysis to calculate polygenic scores, estimates of the overall genetic risk that they would develop a SUD, for the individuals from which the data was collected.

“We defined variants that had the same direction of effects across different SUDs (i.e., concordant variants) as SUD-shared,” wrote the authors. “In total, we identified 220 loci, including 40 novel loci that were not reported as SUD-associated in previous genome-wide association studies.

“Through gene-based analyses, gene mapping, and gene prioritization, we identified 785 SUD-shared genes. These genes are highly expressed in the amygdala, cortex, hippocampus, hypothalamus, and thalamus; and are primarily highly expressed in neuronal cells, suggesting that more brain regions may be involved in SUDs than previously reported.”

The researchers were able to pinpoint several genes that are associated with a greater risk of developing alcohol, cannabis, opioid and tobacco use disorders. They also found that these shared genes were active in brain regions known to play a role in the regulation of emotions, memory and reward-seeking behavior.

“Concordant variants explained 56–96% of the SNP heritability of each SUD in the 1kg-EUR-like sample,” wrote Lai, Zhang and their colleagues. “Furthermore, the top 10% of individuals in the 1kg-EUR-like and 1kg-AMR-like samples with the highest polygenic scores had odds ratios ranging from 1.95–2.87 to develop SUDs, and these polygenic scores could potentially be used to identify high-risk individuals.”

After they further elucidated the genetic underpinning of SUDs, Lai, Zhang and their colleagues analyzed a dataset of existing pharmacological drugs, to determine whether any of these drugs targeted the genes they identified. Ultimately, they were able to identify 7 medications that could potentially be repurposed for the treatment of SUDs and that target genes that were linked to the compulsive use of various substances.

“We identified seven drugs that target SUD-share genes, highlighting their potential for repurposing in the treatment of SUDs,” concluded the authors. “Together, these findings advance our understanding of the genetic architecture underlying SUDs and point to promising future prevention and treatment strategies.”

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