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The relationship between cannabis and schizophrenia: a genetically informed perspective

Research output: Contribution to journalArticlepeer-review

Emma C. Johnson, Alexander S. Hatoum, Joseph D. Deak, Renato Polimanti, Robin M. Murray, Howard J. Edenberg, Joel Gelernter, Marta Di Forti, Arpana Agrawal

Original languageEnglish
Pages (from-to)3227-3234
Number of pages8
Issue number11
Accepted/In press2021
PublishedNov 2021

Bibliographical note

Funding Information: E.C.J. acknowledges support from National Institute on Alcohol Abuse and Alcoholism (grant F32AA027435). A.A. acknowledges National Institute on Drug Abuse (grant K02DA032573). J.D.D. acknowledges National Institute on Alcohol Abuse and Alcoholism (grant T32AA028259). A.S.H. acknowledges T32DA007261. R.P. acknowledges National Institute on Drug Abuse (grant R21DA047527). We thank National Institute of Mental Health (grant MH109532) for supporting the work of the Psychiatric Genomics Consortium's Substance Use Disorders Working group and for support to A.A., H.J.E. and J.G. We thank Drs Raymond Walters, Dongbing Lai and Hang Zhou for their feedback on these analyses. Publisher Copyright: © 2021 Society for the Study of Addiction Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


Background and Aims: While epidemiological studies support a role for heavy, high-potency cannabis use on first-episode psychosis, genetic models of causation suggest reverse causal effects of schizophrenia on cannabis use liability. We estimated the genetic relationship between cannabis use disorder (CUD) and schizophrenia (SCZ) and tested whether liability for CUD is causally associated with increased liability to SCZ while adjusting for tobacco smoking. Design: This study used summary statistics from published genome-wide association studies (GWAS). We used genomic structural equation modeling, latent causal variable analysis, and multivariable Mendelian randomization to examine genetic relationships between CUD, cannabis ever-use, ever-smoked tobacco regularly, nicotine dependence and SCZ, and to test for a causal relationship between liability to CUD and liability to SCZ. Setting: Genome-wide association studies were published previously as part of international consortia. Participants: Sample sizes of the GWAS summary statistics used in this study ranged from 161 405 to 357 806 individuals of European ancestry. Measurements: Genome-wide summary statistics for CUD and SCZ were the primary measurements, while summary statistics for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence were included as additional variables in the genomic structural equation models and the multivariable Mendelian randomization analyses. Findings: Genetic liability to CUD was significantly associated with SCZ [β = 0.29, 95% confidence interval (CI) = 0.11, 0.46, P = 0.001], even when accounting for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence as simultaneous predictors. We found mixed evidence of a causal relationship, with the latent causal variable analysis finding no evidence of causality (genetic causality proportion = −0.08, 95% CI = −0.40, 0.23, P = 0.87) but the multivariable Mendelian randomization analyses suggesting a significant, risk-increasing effect of CUD on liability to SCZ (β = 0.10, 95% CI = 0.02, 0.18, P = 0.02), accounting for the additional risk factors (cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence). Conclusions: Genetic liability for cannabis use disorder appears to be robustly associated with schizophrenia, above and beyond tobacco smoking and cannabis ever-use, with mixed evidence to support a causal relationship between cannabis use disorder and schizophrenia.

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