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

Nature Neurosciencevolume 21pages11611170 (2018) | Download Citation

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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Acknowledgements

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).

Contributors to the 23andMe Research Team

M. Agee, B. Alipanahi, A. Auton, R. K. Bell, K. Bryc, S. L. Elson, P. Fontanillas, N. A. Furlotte, D. A. Hinds, K. E. Huber, A. Kleinman, N. K. Litterman, J. C. McCreight, M. H. McIntyre, J. L. Mountain, E. S. Noblin, C. A. M. Northover, S. J. Pitts, J. Fah Sathirapongsasuti, O. V. Sazonova, J. F. Shelton, S. Shringarpure, C. Tian, J. Y. Tung, V. Vacic and C.H. Wilson.

Contributors to the International Cannabis Consortium

S. Stringer, C. C. Minica, K. J. H. Verweij, H. Mbarek, M. Bernard, J. Derringer, K. R. van Eijk, J. D. Isen, A. Loukola, D. F. Maciejewski, E. Mihailov, P. J. van der Most, C. Sánchez-Mora, L. Roos, R. Sherva, R. Walters, J.J. Ware, A. Abdellaoui, T. B. Bigdeli, S. J. T. Branje, S. A. Brown, M. Bruinenberg, M. Casas, T. Esko, I. Garcia-Martinez, S. D. Gordon, J. M. Harris, C. A. Hartman, A. K. Henders, A. C. Heath, I. B. Hickie, M. Hickman, C. J. Hopfer, J. J. Hottenga, A. C. Huizink, D. E. Irons, R. S. Kahn, T. Korhonen, H. R. Kranzler, K. Krauter, P. A. C. van Lier, G. H. Lubke, P. A. F. Madden, R. Mägi, M. K. McGue, S. E. Medland, W. H. J. Meeus, M. B. Miller, G. W. Montgomery, M. G. Nivard, I. M. Nolte, A. J. Oldehinkel, Z. Pausova, B. Qaiser, L. Quaye, J. A. Ramos-Quiroga, V. Richarte, R. J. Rose, J. Shin, M. C. Stallings, A. I. Stiby, T. L. Wall, M. J. Wright, H. M. Koot, T. Paus, J. K. Hewitt, M. Ribasés, J. Kaprio, M. P. M. Boks, H. Snieder, T. Spector, M. R. Munafò, A. Metspalu, J. Gelernter, D. I. Boomsma, W. G. Iacono, N. G. Martin, N. A. Gillespie, E. M. Derks and J. M. Vink.

Author information

Author notes

  1. These authors contributed equally: Joëlle A. Pasman, Karin J. H. Verweij.

  2. These authors jointly supervised: Nathan A. Gillespie, Eske M. Derks, Jacqueline M. Vink.

  3. A list of 23andMe Research Team members appears at the end of the paper.

  4. Substance Use Disorders Working Group of the Psychiatric Genomics Consortium.

  5. A list of International Cannabis Consortium members appears at the end of the paper.

Affiliations

  1. Behavioural Science Institute, Radboud University, Nijmegen, The Netherlands

    • Joëlle A. Pasman
    • , Karin J. H. Verweij
    •  & Jacqueline M. Vink
  2. Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands

    • Karin J. H. Verweij
    •  & Abdel Abdellaoui
  3. Genetic Epidemiology, Statistical Genetics, and Translational Neurogenomics Laboratories, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    • Zachary Gerring
    • , Jue-Sheng Ong
    • , Nicholas G. Martin
    • , Stuart MacGregor
    • , Nathan A. Gillespie
    •  & Eske M. Derks
  4. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    • Sven Stringer
    •  & Danielle Posthuma
  5. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    • Sandra Sanchez-Roige
    •  & Abraham A. Palmer
  6. MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK

    • Jorien L. Treur
    •  & Marcus R. Munafò
  7. Department of Biological Psychology/Netherlands Twin Register, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    • Michel G. Nivard
    • , Bart M. L. Baselmans
    • , Hill F. Ip
    • , Matthijs D. van der Zee
    • , Meike Bartels
    •  & Dorret I. Boomsma
  8. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK

    • Felix R. Day
    •  & John R. B. Perry
  9. 23andMe, Inc., Mountain View, CA, USA

    • Pierre Fontanillas
    •  & Sarah L. Elson
  10. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA

    • Harriet de Wit
  11. Vanderbilt Genetics Institute; Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA

    • Lea K. Davis
  12. Peter Boris Centre for Addictions Research and Michael G. DeGroote Centre for Medicinal Cannabis Research, McMaster University/St. Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada

    • James MacKillop
  13. Department of Psychology, University of Illinois Urbana-Champaign, Champaign, IL, USA

    • Jaime L. Derringer
  14. Department of Youth and Family, Utrecht University, Utrecht, the Netherlands

    • Susan J. T. Branje
    •  & Wim Meeus
  15. Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    • Catharina A. Hartman
    •  & A. J. Oldehinkel
  16. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

    • Andrew C. Heath
    •  & Pamela A. F. Madden
  17. Department of Developmental Psychology and EMGO Institute for Health and Care Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    • Pol A. C. van Lier
  18. Estonian Genome Center, University of Tartu, Tartu, Estonia

    • Reedik Mägi
  19. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia

    • Grant W. Montgomery
  20. Hospital for Sick Children, Toronto, Ontario, Canada

    • Zdenka Pausova
  21. Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain

    • Josep A. Ramos-Quiroga
    •  & Marta Ribases
  22. Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain

    • Josep A. Ramos-Quiroga
    •  & Marta Ribases
  23. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain

    • Josep A. Ramos-Quiroga
    •  & Marta Ribases
  24. Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

    • Josep A. Ramos-Quiroga
  25. Rotman Research Institute, Baycrest, Toronto, Ontario, Canada

    • Tomas Paus
  26. Departments of Psychology and Psychiatry, University of Toronto, Toronto, Ontario, Canada

    • Tomas Paus
  27. Institute for Molecular Medicine Finland FIMM, HiLIFE Unit, University of Helsinki, Helsinki, Finland

    • Jaakko Kaprio
  28. Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands

    • Marco P. M. Boks
  29. Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK

    • Jordana T. Bell
    •  & Tim D. Spector
  30. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    • Joel Gelernter
  31. Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA

    • Abraham A. Palmer
  32. UK Centre for Tobacco and Alcohol Studies and School of Experimental Psychology, University of Bristol, Bristol, UK

    • Marcus R. Munafò
  33. Department of Psychiatry, Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA

    • Nathan A. Gillespie

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Consortia

  1. the 23andMe Research Team

    1. The Substance Use Disorders Working Group of the Psychiatric Genomics Consortium

      1. International Cannabis Consortium

        Contributions

        K.J.H.V., E.M.D. and J.M.V. were responsible for the study concept and the design of the study. I.C.C. contributed existing genome-wide summary data from the International Cannabis Consortium. The PGC-SUD group provided summary statistics of the cannabis dependence GWAS. S.S., S.S.-R., M.G.N., B.M.L.B., J.-S.O., H.F.I., M.D.v.d.Z., M.B., F.R.D., P.F., S.M., J.R.B.P., A.A.P. and D.P. performed or supervised genome-wide association analyses. J.A.P. performed the quality control and meta-analysis of genome-wide association studies, under supervision of K.J.H.V., B.M.L.B. and J.M.V. J.A.P., K.J.H.V., Z.G., J.L.T., A.A., M.R.M. and E.M.D. contributed to secondary analyses of the data. J.A.P., K.J.H.V., Z.G., N.A.G., E.M.D. and J.M.V. wrote the manuscript. J.L.D., S.J.T.B., C.A.H., A.C.H., P.A.C.v.L., P.A.F.M., R.M., W.M., G.W.M., A.J.O., Z.P., J.A.R.-Q., T.P., M.R., J.K., M.P.M.B., J.T.B., T.D.S., J.G., D.I.B. and N.G.M. contributed to data acquisition of the samples in the International Cannabis Consortium. S.L.E., H.d.W., L.K.D. and J.M.K. contributed to data acquisition and analysis for the 23andMe dataset. All authors provided critical revision of the manuscript for important intellectual content.

        Competing interests

        P.F., S.L.E. and members of the 23andMe Research Team are employees of 23andMe Inc. J.A.R.-Q. was on the speakers’ bureau and/or acted as consultant for Eli Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, BRAINGAZE, Sincrolab and Rubió in the last 5 years. He also received travel awards (air tickets and hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire and Eli Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the last 5 years: Eli Lilly, Lundbeck, Janssen- Cilag, Actelion, Shire, Ferrer and Rubió.

        Corresponding author

        Correspondence to Jacqueline M. Vink.

        Supplementary information

        1. Supplementary Text and Figures

          Supplementary Figures 1–10

        2. Reporting Summary

        3. Supplementary Table 1

          All genome-wide significant SNP associations in the meta-analysis

        4. Supplementary Table 2

          Independent genome-wide significant associations with lifetime cannabis use in the UK Biobank sample

        5. Supplementary Table 3

          Description of the genome-wide significant associations in the gene-based test of association and the S-PrediXcan analysis, with a short (non-comprehensive) overview of relevant literature findings on gene–phenotype associations

        6. Supplementary Table 4

          Significant S-PrediXcan associations after correction for multiple testing

        7. Supplementary Table 5

          Summary of S-PrediXcan associations by target gene

        8. Supplementary Table 6

          Results from LD score regression analysis: genetic correlations between lifetime cannabis use and various traits of interest

        9. Supplementary Table 7

          SNPs included in the genetic instruments used for bidirectional two-sample Mendelian randomization analyses between lifetime cannabis use and schizophrenia diagnosis

        10. Supplementary Table 8

          Cochran's heterogeneity statistic (Q) for inverse-variance-weighted (IVW) bidirectional two-sample Mendelian randomization analyses between lifetime cannabis use and schizophrenia diagnosis

        11. Supplementary Table 9

          I2 statistic for the heterogeneity between genetic variants in an instrument for the MR-Egger SIMEX analysis

        12. Supplementary Table 10

          MR-Egger SIMEX intercept, indicating degree of horizontal pleiotropy, for bidirectional two-sample Mendelian randomization analyses between lifetime cannabis use and schizophrenia diagnosis

        13. Supplementary Table 11

          Methodological details of the individual GWASs

        14. Supplementary Table 12

          quality control steps in the individual GWASs

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        DOI

        https://doi.org/10.1038/s41593-018-0206-1