First genome-wide significant gene identified for cannabis use disorder risk
A large genetic study identified CHRNA2, a gene encoding a nicotinic receptor subunit, as the first genome-wide significant risk locus for cannabis use disorder, with replication in an independent population.
Quick Facts
What This Study Found
A variant (rs56372821) near the CHRNA2 gene reached genome-wide significance for cannabis use disorder risk (P = 9.31 x 10^-12) and replicated independently (P = 3.27 x 10^-3). Higher genetic loading for cognitive performance variants was associated with decreased CUD risk.
Key Numbers
Discovery: 2,387 cases, 48,985 controls. Replication: 5,501 cases, 301,041 controls. Lead variant P-value: 9.31 x 10^-12. Twin heritability estimates for CUD: 51-70%. Cannabis is the most frequently used illicit substance worldwide; ~1 in 10 users become dependent.
How They Did This
Genome-wide association study of 2,387 CUD cases and 48,985 controls, with replication in 5,501 cases and 301,041 controls. Gene expression analysis and polygenic scoring for cognitive traits were also performed.
Why This Research Matters
This is the first robustly replicated genetic variant for cannabis use disorder. Understanding the biological pathways involved could lead to targeted prevention or treatment strategies, and the cholinergic connection links cannabis addiction biology to nicotine pathways.
The Bigger Picture
Finding that a nicotinic receptor gene is involved in cannabis dependence risk suggests overlapping biology between cannabis and nicotine addiction. The cognitive performance connection also hints that the same genetic factors influencing thinking ability may protect against developing cannabis use disorder.
What This Study Doesn't Tell Us
GWAS identifies associations, not mechanisms. The identified variant explains only a small fraction of CUD heritability. European-ancestry populations were overrepresented, limiting generalizability. Environmental factors interacting with genetic risk were not captured.
Questions This Raises
- ?How does CHRNA2 expression in the brain specifically increase vulnerability to cannabis dependence?
- ?Could medications targeting nicotinic receptors help treat cannabis use disorder?
- ?What additional genetic variants contribute to the remaining unexplained heritability?
Trust & Context
- Key Stat:
- First genome-wide significant gene for cannabis use disorder, replicated in 300,000+ people
- Evidence Grade:
- Strong: large sample sizes with independent replication, genome-wide significance threshold, and gene expression validation.
- Study Age:
- Published in 2019 in Nature Neuroscience.
- Original Title:
- Genome-wide association study implicates CHRNA2 in cannabis use disorder.
- Published In:
- Nature neuroscience, 22(7), 1066-1074 (2019)
- Authors:
- Demontis, Ditte(4), Rajagopal, Veera Manikandan, Thorgeirsson, Thorgeir E(2), Als, Thomas D, Grove, Jakob, Leppälä, Kalle, Gudbjartsson, Daniel F, Pallesen, Jonatan, Hjorthøj, Carsten, Reginsson, Gunnar W, Tyrfingsson, Thorarinn, Runarsdottir, Valgerdur, Qvist, Per, Christensen, Jane Hvarregaard, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Huckins, Laura M, Stahl, Eli A, Timmermann, Allan, Agerbo, Esben, Hougaard, David M, Werge, Thomas, Mors, Ole, Mortensen, Preben Bo, Nordentoft, Merete, Daly, Mark J, Stefansson, Hreinn, Stefansson, Kari, Nyegaard, Mette, Børglum, Anders D
- Database ID:
- RTHC-02006
Evidence Hierarchy
A snapshot of a population at one point in time.
What do these levels mean? →Frequently Asked Questions
Is cannabis addiction genetic?
Partly. Twin studies estimate 51-70% of the risk for cannabis use disorder is heritable. This study identified the first specific gene variant, in CHRNA2, that contributes to that genetic risk.
What does a nicotine receptor gene have to do with cannabis?
CHRNA2 encodes a subunit of nicotinic acetylcholine receptors in the brain. Its involvement suggests cannabis and nicotine addiction may share some biological pathways, even though they act on different primary receptor systems.
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Cite This Study
https://rethinkthc.com/research/RTHC-02006APA
Demontis, Ditte; Rajagopal, Veera Manikandan; Thorgeirsson, Thorgeir E; Als, Thomas D; Grove, Jakob; Leppälä, Kalle; Gudbjartsson, Daniel F; Pallesen, Jonatan; Hjorthøj, Carsten; Reginsson, Gunnar W; Tyrfingsson, Thorarinn; Runarsdottir, Valgerdur; Qvist, Per; Christensen, Jane Hvarregaard; Bybjerg-Grauholm, Jonas; Bækvad-Hansen, Marie; Huckins, Laura M; Stahl, Eli A; Timmermann, Allan; Agerbo, Esben; Hougaard, David M; Werge, Thomas; Mors, Ole; Mortensen, Preben Bo; Nordentoft, Merete; Daly, Mark J; Stefansson, Hreinn; Stefansson, Kari; Nyegaard, Mette; Børglum, Anders D. (2019). Genome-wide association study implicates CHRNA2 in cannabis use disorder.. Nature neuroscience, 22(7), 1066-1074. https://doi.org/10.1038/s41593-019-0416-1
MLA
Demontis, Ditte, et al. "Genome-wide association study implicates CHRNA2 in cannabis use disorder.." Nature neuroscience, 2019. https://doi.org/10.1038/s41593-019-0416-1
RethinkTHC
RethinkTHC Research Database. "Genome-wide association study implicates CHRNA2 in cannabis ..." RTHC-02006. Retrieved from https://rethinkthc.com/research/demontis-2019-genomewide-association-study-implicates
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.