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A study published in Nature Mental Health has shed new light on the genetic connection between attention-deficit hyperactivity disorder (ADHD) and cannabis use disorder. Researchers identified dozens of genetic loci shared between ADHD and cannabis use disorder. The research provides a better understanding of the genetic overlap between ADHD and cannabis-related behaviors and offers potential insights into early identification of those at high risk for developing cannabis use disorder.
Attention-deficit hyperactivity disorder (ADHD) is a common neurodevelopmental condition that typically begins in childhood and often persists into adulthood. Characterized by inattention, hyperactivity, and impulsivity that exceed age-appropriate levels, ADHD can significantly impair daily functioning and quality of life. It affects about 5% of children and 2.5% of adults worldwide. The disorder has a strong genetic component, with heritability estimates around 74%, and previous studies have shown that common genetic variations account for a significant portion of the risk.
Among substance use disorders, cannabis use disorder is particularly prevalent in individuals with ADHD, especially in adolescents and young adults. Research has shown that people with ADHD are 10 times more likely to develop substance use disorders compared to those without the condition. Externalizing behaviors like impulsivity and risk-taking, which are hallmark features of ADHD, are thought to increase susceptibility to cannabis use and eventual dependence.
The researchers behind the new study hypothesized that shared genetic factors might also contribute to this comorbidity and sought to investigate these links using large-scale genetic data. By comparing the genetic architecture of ADHD with cannabis use disorder and general cannabis use, they aimed to identify overlapping genetic factors, clarify how ADHD contributes to cannabis use disorder risk, and explore whether these genetic pathways differ for cannabis use versus cannabis use disorder.
To investigate, the researchers conducted a genome-wide association study, a research approach used to identify genetic variations associated with specific diseases or traits. By analyzing the genomes of large groups of individuals, some with and some without a particular condition, researchers can pinpoint genetic variants that are more common in those with the condition.
This large-scale study analyzed genetic data from individuals of European ancestry, leveraging datasets from existing GWAS meta-analyses of ADHD, cannabis use disorder, and cannabis use. Specifically, the ADHD data included 38,691 individuals diagnosed with the disorder and 186,843 controls, the cannabis use disorder dataset included 42,281 individuals with the condition and 843,744 controls, and the cannabis use dataset comprised 162,082 individuals reporting lifetime cannabis use.
The researchers identified 36 genetic loci shared between ADHD and cannabis use disorder, with these loci demonstrating significant activity in brain tissues and across brain developmental stages. This contrasts with ADHD and general cannabis use, which shared only 10 genetic loci and showed no evidence of consistent brain-specific gene expression.
Among the key findings, the DRD2 gene, which encodes a dopamine receptor, emerged as a significant risk factor for both ADHD and cannabis use disorder. This is particularly noteworthy given dopamine’s established role in both ADHD and addiction.
The study also found that the genetic regions shared by both ADHD and cannabis use disorder were more likely to affect genes related to brain function and development compared to the regions shared by both ADHD and general cannabis use. This suggests that the genetic connection between attention-deficit hyperactivity disorder and cannabis use disorder is stronger and more biologically significant.
To explore individual risk, the researchers employed polygenic risk scores (PGS), which estimate an individual’s genetic susceptibility to a condition based on the cumulative effect of multiple genetic variants. Individuals with ADHD who had a high PGS for cannabis use disorder were found to have an absolute risk of 22% for developing cannabis use disorder, compared to a risk of just 1.6% in controls without ADHD.
The risk was particularly pronounced in men, who were 10% more likely than women to develop cannabis use disorder in the highest-risk group. These findings highlight the potential for PGS to predict individual risk for cannabis use disorder among people with ADHD, offering a tool for early identification and prevention strategies.
The researchers also examined rare genetic variants and found that individuals with both ADHD and cannabis use disorder had a higher burden of rare deleterious mutations compared to those with ADHD alone. These rare mutations were particularly concentrated in genes that are more evolutionarily tolerant to loss-of-function changes, indicating that genetic susceptibility to cannabis use disorder may involve both common and rare genetic factors.
Interestingly, the researchers also uncovered significant differences in the genetic overlap of ADHD with cannabis use disorder versus general cannabis use. While ADHD and general cannabis use shared some genetic variants, these overlaps were weaker and less specific to brain function than those associated with ADHD and cannabis use disorder. This supports the idea that the genetic mechanisms underlying cannabis use as a behavior differ from those driving cannabis dependence as a disorder.
But as with all research, there are some caveats to consider. The data were derived from individuals of European ancestry, limiting the generalizability of the results to other populations. Additionally, the definition of cannabis use was broad, encompassing individuals with varying levels of use, which may have introduced heterogeneity in the analyses. Future research could refine the definitions of cannabis use and explore the impact of environmental factors and comorbid conditions, such as conduct disorder or schizophrenia.
The study, “Shared genetics of ADHD, cannabis use disorder and cannabis use and prediction of cannabis use disorder in ADHD,” was authored by Trine Tollerup Nielsen, Jinjie Duan, Daniel F. Levey, G. Bragi Walters, Emma C. Johnson, Thorgeir Thorgeirsson, VA Million Veteran Program, Thomas Werge, Preben Bo Mortensen, Hreinn Stefansson, Kari Stefansson, David M. Hougaard, Arpana Agrawal, Joel Gelernter, Jakob Grove, Anders D. Børglum, and Ditte Demontis.
