The largest GWAS of cannabis use identified 8 genetic variants, found 11% heritability, and showed schizophrenia risk causally influences cannabis use
A GWAS of 184,765 individuals identified 8 significant genetic variants for lifetime cannabis use in 6 genomic regions, with the strongest finding at CADM2 (linked to risk-taking), 11% SNP heritability, and Mendelian randomization evidence that schizophrenia risk causally increases cannabis use.
Quick Facts
What This Study Found
In the largest GWAS of lifetime cannabis use to date, researchers analyzed 184,765 individuals and identified eight genome-wide significant SNPs in six genomic regions.
All measured genetic variants combined explained 11% of the variance in cannabis use.
Gene-based tests revealed 35 significant genes in 16 regions. The strongest finding was CADM2, previously associated with substance use and risk-taking behavior.
S-PrediXcan analyses showed 21 genes had different expression levels between cannabis users and non-users.
Significant genetic correlations were found with 14 of 25 tested traits, including smoking, alcohol use, schizophrenia, and risk-taking.
Mendelian randomization analysis provided evidence for a causal positive influence of schizophrenia risk on cannabis use. This means genetic liability for schizophrenia increases the probability of using cannabis, not just the reverse.
Key Numbers
N = 184,765. 8 genome-wide significant SNPs in 6 regions. 35 significant genes via gene-based tests. 11% variance explained by all SNPs. 21 genes with differential expression. 14 significant genetic correlations with other traits. CADM2 was the strongest finding.
How They Did This
Genome-wide association meta-analysis. N = 184,765. Gene-based tests (MAGMA). S-PrediXcan transcriptomic analyses. LD score regression for genetic correlations. Mendelian randomization for causal inference.
Why This Research Matters
The Mendelian randomization finding is a game-changer for the cannabis-schizophrenia debate. While epidemiology has long shown that cannabis users have higher psychosis risk, this genetic analysis shows the arrow can also point the other direction: people genetically predisposed to schizophrenia are more likely to use cannabis, possibly as self-medication.
The Bigger Picture
This study reframes the cannabis-psychosis relationship as bidirectional: cannabis may increase psychosis risk AND psychosis risk increases cannabis use. Understanding both directions is essential for developing effective prevention and treatment strategies.
What This Study Doesn't Tell Us
European-ancestry cohorts only. Lifetime cannabis use is a binary measure that does not capture dose, frequency, or recency. Mendelian randomization assumptions may be violated. 11% variance explained means most genetic variance is still unaccounted for.
Questions This Raises
- ?How do these genetic variants affect brain function to influence cannabis use?
- ?Can polygenic risk scores identify individuals at highest risk for both cannabis use and psychosis?
- ?Would genetic counseling about cannabis risk be feasible or ethical?
Trust & Context
- Key Stat:
- Schizophrenia risk causally increases cannabis use (Mendelian randomization)
- Evidence Grade:
- Strong. Published in Nature Neuroscience with the largest sample to date, rigorous statistical methods, and novel causal inference approach.
- Study Age:
- Published in 2018 in Nature Neuroscience. Subsequent GWAS with even larger samples have continued to build on these findings.
- Original Title:
- GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.
- Published In:
- Nature neuroscience, 21(9), 1161-1170 (2018)
- Authors:
- Pasman, Joëlle A, Verweij, Karin J H(8), Gerring, Zachary, Stringer, Sven, Sanchez-Roige, Sandra, Treur, Jorien L, Abdellaoui, Abdel, Nivard, Michel G, Baselmans, Bart M L, Ong, Jue-Sheng, Ip, Hill F, van der Zee, Matthijs D, Bartels, Meike, Day, Felix R, Fontanillas, Pierre, Elson, Sarah L, de Wit, Harriet, Davis, Lea K, MacKillop, James, Derringer, Jaime L, Branje, Susan J T, Hartman, Catharina A, Heath, Andrew C, van Lier, Pol A C, Madden, Pamela A F, Mägi, Reedik, Meeus, Wim, Montgomery, Grant W, Oldehinkel, A J, Pausova, Zdenka, Ramos-Quiroga, Josep A, Paus, Tomas, Ribases, Marta, Kaprio, Jaakko, Boks, Marco P M, Bell, Jordana T, Spector, Tim D, Gelernter, Joel, Boomsma, Dorret I, Martin, Nicholas G, MacGregor, Stuart, Perry, John R B, Palmer, Abraham A, Posthuma, Danielle, Munafò, Marcus R, Gillespie, Nathan A, Derks, Eske M, Vink, Jacqueline M
- Database ID:
- RTHC-01785
Evidence Hierarchy
Combines results from multiple studies to find an overall pattern.
What do these levels mean? →Frequently Asked Questions
Does this mean schizophrenia causes cannabis use?
The Mendelian randomization analysis found that genetic liability for schizophrenia increases the probability of cannabis use. This suggests that some of the observed association between cannabis and psychosis is because people predisposed to schizophrenia are more likely to use cannabis, not solely because cannabis causes psychosis. The relationship appears to be bidirectional.
What is CADM2?
CADM2 (Cell Adhesion Molecule 2) is a gene involved in brain cell communication. It has been previously linked to risk-taking behavior and substance use in other studies. Its association with cannabis use suggests that general tendencies toward novelty-seeking or risk-taking may partly drive cannabis initiation.
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Cite This Study
https://rethinkthc.com/research/RTHC-01785APA
Pasman, Joëlle A; Verweij, Karin J H; Gerring, Zachary; Stringer, Sven; Sanchez-Roige, Sandra; Treur, Jorien L; Abdellaoui, Abdel; Nivard, Michel G; Baselmans, Bart M L; Ong, Jue-Sheng; Ip, Hill F; van der Zee, Matthijs D; Bartels, Meike; Day, Felix R; Fontanillas, Pierre; Elson, Sarah L; de Wit, Harriet; Davis, Lea K; MacKillop, James; Derringer, Jaime L; Branje, Susan J T; Hartman, Catharina A; Heath, Andrew C; van Lier, Pol A C; Madden, Pamela A F; Mägi, Reedik; Meeus, Wim; Montgomery, Grant W; Oldehinkel, A J; Pausova, Zdenka; Ramos-Quiroga, Josep A; Paus, Tomas; Ribases, Marta; Kaprio, Jaakko; Boks, Marco P M; Bell, Jordana T; Spector, Tim D; Gelernter, Joel; Boomsma, Dorret I; Martin, Nicholas G; MacGregor, Stuart; Perry, John R B; Palmer, Abraham A; Posthuma, Danielle; Munafò, Marcus R; Gillespie, Nathan A; Derks, Eske M; Vink, Jacqueline M. (2018). GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.. Nature neuroscience, 21(9), 1161-1170. https://doi.org/10.1038/s41593-018-0206-1
MLA
Pasman, Joëlle A, et al. "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.." Nature neuroscience, 2018. https://doi.org/10.1038/s41593-018-0206-1
RethinkTHC
RethinkTHC Research Database. "GWAS of lifetime cannabis use reveals new risk loci, genetic..." RTHC-01785. Retrieved from https://rethinkthc.com/research/pasman-2018-gwas-of-lifetime-cannabis
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.