The impact of schizophrenia genetic load and heavy cannabis use on the risk of psychotic disorder in the EU-GEI case-control and UK Biobank studies

Isabelle Austin-Zimmerman¹, Edoardo Spinazzola^{2

3}, Diego Quattrone^{1

2}, Beatrice Wu-Choi⁴, Giulia Trotta^{1

2}, Zhikun Li¹, Emma Johnson⁵, Alexander L Richards⁶, Tom P Freeman^{7

8}, Giada Tripoli^{3

9}, Charlotte Gayer-Anderson¹⁰, Victoria Rodriguez³, Hannah E Jongsma^{11

12}, Laura Ferraro⁹, Caterina La Cascia⁹, Sarah Tosato¹³, Ilaria Tarricone¹⁴, Domenico Berardi¹⁴, Elena Bonora¹⁴, Marco Seri¹⁴, Giuseppe D'Andrea¹⁴, Andrei Szöke¹⁵, Celso Arango¹⁶, Julio Bobes¹⁷, Julio Sanjuán¹⁸, Jose Luis Santos¹⁹, Manuel Arrojo¹⁹, Eva Velthorst²⁰, Miguel Bernardo²¹, Cristina Marta Del-Ben²², Paulo Rossi Menezes^{23

24}, Jean-Paul Selten¹², Peter B Jones^{11

25}, James B Kirkbride²⁶, Bart P F Rutten⁸, Andrea Tortelli²⁷, Pierre-Michel Llorca^{15

27}, Lieuwe de Haan²⁸, Simona Stilo^{1

29}, Daniele La Barbera⁹, Antonio Lasalvia¹³, Franck Schurnhoff³⁰, Baptiste Pignon³⁰, Jim van Os³¹, Michael Lynskey³², Craig Morgan¹⁰; EU-GEI WP2 Group; Michael O' Donovan⁶, Cathryn M Lewis^{1

33}, Pak C Sham^{1

34

35}, Robin M Murray^{2

3}, Evangelos Vassos¹, Marta Di Forti^{1

2

33}

Affiliations

¹ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
² South London and Maudsley NHS Mental Health Foundation Trust, London, UK.
³ Department of Psychosis Studies, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
⁴ Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai NYC, New York, NY, USA.
⁵ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
⁶ Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff CF24 4HQ, UK.
⁷ Addiction and Mental Health Group (AIM), Department of Psychology, University of Bath, Bath, UK.
⁸ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, South Limburg Mental Health Research and Teaching Network, Maastricht University Medical Centre, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
⁹ Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Via G. La Loggia 1, 90129 Palermo, Italy.
¹⁰ ESRC Centre for Society and Mental Health and Health Service and Population Research Department, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
¹¹ Department of Psychiatry, University of Cambridge, Herchel Smith Building for Brain & Mind Sciences, Forvie Site, Robinson Way, Cambridge CB2 0SZ, UK.
¹² Rivierduinen Institute for Mental Health Care, Sandifortdreef 19, 2333 ZZ Leiden, The Netherlands.
¹³ Section of Psychiatry, Azienda Ospedaliera Universitaria Integrata di Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy.
¹⁴ Department of Medical and Surgical Science, Psychiatry Unit, Alma Mater Studiorum Università di Bologna, Viale Pepoli 5, 40126 Bologna, Italy.
¹⁵ INSERM, U955, Equipe 15, 51 Avenue de Maréchal de Lattre de Tassigny, 94010 Créteil, France.
¹⁶ Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, School of Medicine, Universidad Complutense, Madrid, Spain.
¹⁷ Department of Medicine, Psychiatry Area, School of Medicine, Universidad de Oviedo, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), C/Julián Clavería s/n, 33006 Oviedo, Spain.
¹⁸ Department of Psychiatry, School of Medicine, Universidad de Valencia, CIBERSAM, Valencia, Spain.
¹⁹ Department of Psychiatry, Psychiatric Genetic Group, Instituto de Investigación Sanitaria de Santiago de Compostela, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain.
²⁰ Department of Psychiatry, Mount Sinai School of Medicine, Icahn School of Medicine, New York, NY, USA.
²¹ Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic, Department of Medicine, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
²² Division of Psychiatry, Department of Neuroscience and Behaviour, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brasil.
²³ Departamento de Medicina Preventiva, Faculdade de Medicina, Universidade de São Paulo, Avenida Doutor Arnaldo 455, CEP 01246-903 São Paulo, Brasil.
²⁴ Núcleo de Pesquina em Saúde Mental Populacional, Universidade de São Paulo, Avenida Doutor Arnaldo 455, CEP 01246-903 São Paulo, Brasil.
²⁵ CAMEO Early Intervention Service, Cambridgeshire & Peterborough NHS Foundation Trust, Cambridge CB21 5EF, UK.
²⁶ PsyLife Group, Division of Psychiatry, University College London, London, UK.
²⁷ CMP B CHU, BP 69, 63003 Clermont Ferrand, Cedex 1, France.
²⁸ Department of Psychiatry, Early Psychosis Section, Academic Medical Centre, University of Amsterdam, Meibergdreef 5, 1105 AZ Amsterdam, The Netherlands.
²⁹ Department of Mental Health and Addiction Services, ASP Crotone, Crotone, Italy.
³⁰ Univ Paris Est Creteil (UPEC), AP-HP, Hopitaux Universitaires 'H. Mondor', DMU IMPACT, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, F-94010 Créteil, France.
³¹ Brain Centre Rudolf Magnus, Utrecht University Medical Centre, Utrecht, The Netherlands.
³² Department of Addiction, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
³³ National Institute for Health Research (NIHR), Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK.
³⁴ Department of Psychiatry, The University of Hong Kong, Hong Kong, China.
³⁵ Centre for Genomic Sciences, Li KaShing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

PMID: 39637925
PMCID: PMC11650186
DOI: 10.1017/S0033291724002058

The impact of schizophrenia genetic load and heavy cannabis use on the risk of psychotic disorder in the EU-GEI case-control and UK Biobank studies

Isabelle Austin-Zimmerman et al. Psychol Med. 2024.

. 2024 Dec 6;54(15):1-13.

doi: 10.1017/S0033291724002058. Online ahead of print.

Authors

Affiliations

¹ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
² South London and Maudsley NHS Mental Health Foundation Trust, London, UK.
³ Department of Psychosis Studies, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
⁴ Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai NYC, New York, NY, USA.
⁵ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
⁶ Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff CF24 4HQ, UK.
⁷ Addiction and Mental Health Group (AIM), Department of Psychology, University of Bath, Bath, UK.
⁸ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, South Limburg Mental Health Research and Teaching Network, Maastricht University Medical Centre, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
⁹ Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Via G. La Loggia 1, 90129 Palermo, Italy.
¹⁰ ESRC Centre for Society and Mental Health and Health Service and Population Research Department, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
¹¹ Department of Psychiatry, University of Cambridge, Herchel Smith Building for Brain & Mind Sciences, Forvie Site, Robinson Way, Cambridge CB2 0SZ, UK.
¹² Rivierduinen Institute for Mental Health Care, Sandifortdreef 19, 2333 ZZ Leiden, The Netherlands.
¹³ Section of Psychiatry, Azienda Ospedaliera Universitaria Integrata di Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy.
¹⁴ Department of Medical and Surgical Science, Psychiatry Unit, Alma Mater Studiorum Università di Bologna, Viale Pepoli 5, 40126 Bologna, Italy.
¹⁵ INSERM, U955, Equipe 15, 51 Avenue de Maréchal de Lattre de Tassigny, 94010 Créteil, France.
¹⁶ Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, School of Medicine, Universidad Complutense, Madrid, Spain.
¹⁷ Department of Medicine, Psychiatry Area, School of Medicine, Universidad de Oviedo, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), C/Julián Clavería s/n, 33006 Oviedo, Spain.
¹⁸ Department of Psychiatry, School of Medicine, Universidad de Valencia, CIBERSAM, Valencia, Spain.
¹⁹ Department of Psychiatry, Psychiatric Genetic Group, Instituto de Investigación Sanitaria de Santiago de Compostela, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain.
²⁰ Department of Psychiatry, Mount Sinai School of Medicine, Icahn School of Medicine, New York, NY, USA.
²¹ Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic, Department of Medicine, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
²² Division of Psychiatry, Department of Neuroscience and Behaviour, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brasil.
²³ Departamento de Medicina Preventiva, Faculdade de Medicina, Universidade de São Paulo, Avenida Doutor Arnaldo 455, CEP 01246-903 São Paulo, Brasil.
²⁴ Núcleo de Pesquina em Saúde Mental Populacional, Universidade de São Paulo, Avenida Doutor Arnaldo 455, CEP 01246-903 São Paulo, Brasil.
²⁵ CAMEO Early Intervention Service, Cambridgeshire & Peterborough NHS Foundation Trust, Cambridge CB21 5EF, UK.
²⁶ PsyLife Group, Division of Psychiatry, University College London, London, UK.
²⁷ CMP B CHU, BP 69, 63003 Clermont Ferrand, Cedex 1, France.
²⁸ Department of Psychiatry, Early Psychosis Section, Academic Medical Centre, University of Amsterdam, Meibergdreef 5, 1105 AZ Amsterdam, The Netherlands.
²⁹ Department of Mental Health and Addiction Services, ASP Crotone, Crotone, Italy.
³⁰ Univ Paris Est Creteil (UPEC), AP-HP, Hopitaux Universitaires 'H. Mondor', DMU IMPACT, INSERM, IMRB, Translational Neuropsychiatry, Fondation FondaMental, F-94010 Créteil, France.
³¹ Brain Centre Rudolf Magnus, Utrecht University Medical Centre, Utrecht, The Netherlands.
³² Department of Addiction, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
³³ National Institute for Health Research (NIHR), Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK.
³⁴ Department of Psychiatry, The University of Hong Kong, Hong Kong, China.
³⁵ Centre for Genomic Sciences, Li KaShing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

PMID: 39637925
PMCID: PMC11650186
DOI: 10.1017/S0033291724002058

Abstract

Background: The association between cannabis and psychosis is established, but the role of underlying genetics is unclear. We used data from the EU-GEI case-control study and UK Biobank to examine the independent and combined effect of heavy cannabis use and schizophrenia polygenic risk score (PRS) on risk for psychosis.

Methods: Genome-wide association study summary statistics from the Psychiatric Genomics Consortium and the Genomic Psychiatry Cohort were used to calculate schizophrenia and cannabis use disorder (CUD) PRS for 1098 participants from the EU-GEI study and 143600 from the UK Biobank. Both datasets had information on cannabis use.

Results: In both samples, schizophrenia PRS and cannabis use independently increased risk of psychosis. Schizophrenia PRS was not associated with patterns of cannabis use in the EU-GEI cases or controls or UK Biobank cases. It was associated with lifetime and daily cannabis use among UK Biobank participants without psychosis, but the effect was substantially reduced when CUD PRS was included in the model. In the EU-GEI sample, regular users of high-potency cannabis had the highest odds of being a case independently of schizophrenia PRS (OR daily use high-potency cannabis adjusted for PRS = 5.09, 95% CI 3.08-8.43, p = 3.21 × 10^-10). We found no evidence of interaction between schizophrenia PRS and patterns of cannabis use.

Conclusions: Regular use of high-potency cannabis remains a strong predictor of psychotic disorder independently of schizophrenia PRS, which does not seem to be associated with heavy cannabis use. These are important findings at a time of increasing use and potency of cannabis worldwide.

Keywords: cannabis; first-episode psychosis; high-potency cannabis; polygenic risk score; psychosis; schizophrenia.

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Conflict of interest statement

M. Di Forti reports personal fees from Janssen, outside the submitted work. R. M. Murray reports personal fees from Janssen, Lundbeck, Sunovion, and Otsuka, outside of the submitted work. Dr Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion, and Takeda. All the remaining authors have declared that there are no competing interests in relation to the subject of this study.

Figures

**Figure 1.**
Distribution of schizophrenia PRSs shows an overall increase in PRS for cases compared to controls in the EU-GEI cohort (mean PRS cases = 0.40 ± 1.05, mean PRS controls = 0.17 ± 1.00, p = 2.2 × 10⁻²⁶).

**Figure 2.**
Probability of psychosis case status within EU-GEI cohort as schizophrenia PRS increases, across seven levels of cannabis potency–frequency composite measure.

See this image and copyright information in PMC

References

1. 1000 Genomes Project Consortium. (2010). A map of human genome variation from population scale sequencing. Nature, 467, 1061. doi:10.1038/nature09534 - DOI - PMC - PubMed
1. Agrawal, A., & Lynskey, M. T. (2006). The genetic epidemiology of cannabis use, abuse and dependence. Addiction, 101, 801–812. doi:10.1111/j.1360-0443.2006.01399.x - DOI - PubMed
1. Bharat, C., Webb, P., Wilkinson, Z., McKetin, R., Grebely, J., Farrell, M., … Clark, B. (2023). Agreement between self-reported illicit drug use and biological samples: A systematic review and meta-analysis. Addiction, 118, 1624–1648. doi:10.1111/add.16200 - DOI - PubMed
1. Bigdeli, T. B., Genovese, G., Georgakopoulos, P., Meyers, J. L., Peterson, R. E., Iyegbe, C. O., … Pato, C. N. (2020). Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry. Molecular Psychiatry, 25, 2455–2467. doi:10.1038/s41380-019-0517-y - DOI - PMC - PubMed
1. Brisacier, A.-C., Cadet-Taïrou, A., Díaz Gómez, C., Gandilhon, M., Le Nézet, O., & Lemenier-Jeannet, A. (2015). Drogues, chiffres clés. Paris: Observatoire Français des Drogues et des Toxicomanies. Government document. Retrieved from https://www.ofdt.fr/publications/collections/drogues-et-addictions-chiff...

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The impact of schizophrenia genetic load and heavy cannabis use on the risk of psychotic disorder in the EU-GEI case-control and UK Biobank studies

Affiliations

The impact of schizophrenia genetic load and heavy cannabis use on the risk of psychotic disorder in the EU-GEI case-control and UK Biobank studies

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources