GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia

Sven Stringer; Jorien L Treur; Abdel Abdellaoui; Michel G Nivard; Bart M L Baselmans; Hill F Ip; Matthijs D van der Zee; Meike Bartels; Pol A C van Lier; Dorret I Boomsma; Danielle Posthuma; Eske M Derks; Jacqueline M Vink; 23Andme Research Team

doi:10.1038/s41593-018-0206-1

GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia

Sven Stringer, Jorien L Treur, Abdel Abdellaoui, Michel G Nivard, Bart M L Baselmans, Hill F Ip, Matthijs D van der Zee, Meike Bartels, Pol A C van Lier, Dorret I Boomsma, Danielle Posthuma, Eske M Derks, Jacqueline M Vink^*, 23Andme Research Team

^*Corresponding author for this work

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Abstract

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

Original language	English
Pages (from-to)	1161-1170
Number of pages	10
Journal	Nature Neuroscience
Volume	21
Issue number	9
Early online date	27 Aug 2018
DOIs	https://doi.org/10.1038/s41593-018-0206-1
Publication status	Published - Sept 2018

Funding

We would like to thank the research participants and employees of 23andMe for making this work possible. We gratefully acknowledge the Psychiatric Genomics Consortium contributing studies and the participants in those studies without whom this effort would not have been possible. J.A.P. and J.M.V. are supported by the European Research Council (Beyond the Genetics of Addiction ERC-284167, PI J.M.V.). K.J.H.V. is supported by the Foundation Volksbond Rotterdam. N.A.G. is supported by US National Institutes of Health, National Institute on Drug Abuse R00DA023549. J.L.T. is supported by the Netherlands Organization for Scientific Research (NWO; Rubicon grant 446-16-009). S.M. is supported by an Australian Research Council Fellowship. Statistical analyses were partly carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Organization for Scientific Research (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. M.G.N. is supported by Royal Netherlands Academy of Science Professor Award to D.I.B. (PAH/6635). Part of the computation of this project was funded by NWO Exact Sciences for the application: “Population scale Genetic Analysis” awarded to M.G.N. The genome-wide association analysis on the UK Biobank dataset has been conducted using the UK Biobank resource under application numbers 9905, 16406 and 25331. The Substance Use Disorders Working Group of the Psychiatric Genomics Consortium (PGC-SUD) is supported by funds from NIDA and NIMH to MH109532 and, previously, with analyst support from NIAAA to U01AA008401 (COGA). J.M.’s contributions were partially supported by the Peter Boris Chair in Addictions Research. S.S.-R. was supported by the Frontiers of Innovation Scholars Program (FISP; #3-P3029), the Interdisciplinary Research Fellowship in NeuroAIDS (IRFN; MH081482) and a pilot award from DA037844. R.M. was supported by the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) and the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements No 692065 and 692145. J.K. was supported by Academy Professorship grants by the Academy of Finland (263278, 292782). M.R. is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Spain (CP09/00119 and CPII15/00023).

Funders	Funder number
Dutch Brain Foundation
Foundation Volksbond Rotterdam
Netherlands Organization for Scientific Research
Koninklijke Nederlandse Akademie van Wetenschappen	PAH/6635
National Institutes of Health
National Institute of Mental Health	U01MH109532
National Institute on Drug Abuse	R00DA023549
National Institute on Alcohol Abuse and Alcoholism	U01AA008401, DA037844, 3-P3029, MH081482
Horizon 2020 Framework Programme	692065, 692145
European Commission
European Research Council	ERC-284167
Australian Research Council
Vrije Universiteit Amsterdam
Academy of Finland	263278, 292782
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	446-16-009
Instituto de Salud Carlos III	CP09/00119, CPII15/00023
European Regional Development Fund	2014-2020.4.01.15-0012
National Institute of Development Administration

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

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

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GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophreniaFinal published version, 2.41 MBLicence: Article 25fa Dutch Copyright Act

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Stringer, S., Treur, J. L., Abdellaoui, A., Nivard, M. G., Baselmans, B. M. L., Ip, H. F., van der Zee, M. D., Bartels, M., van Lier, P. A. C., Boomsma, D. I., Posthuma, D., Derks, E. M., Vink, J. M., & 23Andme Research Team (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

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abstract = "Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.",

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Stringer, S, Treur, JL, Abdellaoui, A, Nivard, MG, Baselmans, BML, Ip, HF, van der Zee, MD, Bartels, M, van Lier, PAC, Boomsma, DI , Posthuma, D, Derks, EM, Vink, JM & 23Andme Research Team 2018, 'GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia', Nature Neuroscience, vol. 21, no. 9, pp. 1161-1170. https://doi.org/10.1038/s41593-018-0206-1

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GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia

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