The relationship between cannabis and schizophrenia: a genetically informed perspective

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

doi:10.1111/add.15534

The relationship between cannabis and schizophrenia: a genetically informed perspective

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

42 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	3227-3234
Number of pages	8
Journal	Addiction
Volume	116
Issue number	11
Early online date	19 May 2021
DOIs	https://doi.org/10.1111/add.15534
Publication status	Published - Nov 2021

Keywords

Cannabis
genome-wide association study
genomic structural equation modeling
latent causal variable model
multivariable Mendelian randomization
schizophrenia
tobacco

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/add.15534

Cite this

@article{c6371adcedc64719bae657594fe289fa,

title = "The relationship between cannabis and schizophrenia: a genetically informed perspective",

abstract = "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.",

keywords = "Cannabis, genome-wide association study, genomic structural equation modeling, latent causal variable model, multivariable Mendelian randomization, schizophrenia, tobacco",

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

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: {\textcopyright} 2021 Society for the Study of Addiction Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = nov,

doi = "10.1111/add.15534",

language = "English",

volume = "116",

pages = "3227--3234",

journal = "Addiction",

issn = "0965-2140",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "11",

}

TY - JOUR

T1 - The relationship between cannabis and schizophrenia

T2 - a genetically informed perspective

AU - Johnson, Emma C.

AU - Hatoum, Alexander S.

AU - Deak, Joseph D.

AU - Polimanti, Renato

AU - Murray, Robin M.

AU - Edenberg, Howard J.

AU - Gelernter, Joel

AU - Di Forti, Marta

AU - Agrawal, Arpana

N1 - 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.

PY - 2021/11

Y1 - 2021/11

N2 - 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.

AB - 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.

KW - Cannabis

KW - genome-wide association study

KW - genomic structural equation modeling

KW - latent causal variable model

KW - multivariable Mendelian randomization

KW - schizophrenia

KW - tobacco

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U2 - 10.1111/add.15534

DO - 10.1111/add.15534

M3 - Article

AN - SCOPUS:85105913338

SN - 0965-2140

VL - 116

SP - 3227

EP - 3234

JO - Addiction

JF - Addiction

IS - 11

ER -

The relationship between cannabis and schizophrenia: a genetically informed perspective

Abstract

Keywords

UN SDGs

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