Methylomic signature of current cannabis use in two first-episode psychosis cohorts

Emma L. Dempster; Chloe C.Y. Wong; Joe Burrage; Eilis Hannon; Diego Quattrone; Giulia Trotta; Victoria Rodriguez; Luis Alameda; Edoardo Spinazzola; Giada Tripoli; Isabelle Austin-Zimmerman; Zhikun Li; Charlotte Gayer-Anderson; Tom P. Freeman; Emma C. Johnson; Hannah E. Jongsma; Simona Stilo; Caterina La Cascia; Laura Ferraro; Daniele La Barbera; Antonio Lasalvia; Sarah Tosato; Ilaria Tarricone; Giuseppe D’Andrea; Michela Galatolo; Andrea Tortelli; Maurizio Pompili; Jean Paul Selten; Lieuwe de Haan; Paulo Rossi Menezes; Cristina M. Del Ben; Jose Luis Santos; Manuel Arrojo; Julio Bobes; Julio Sanjuán; Miguel Bernardo; Celso Arango; Peter B. Jones; Gerome Breen; Valeria Mondelli; Paola Dazzan; Conrad Iyegbe; Evangelos Vassos; Craig Morgan; Diptendu Mukherjee; Jim van Os; Bart Rutten; Michael C. O’Donovan; Pak Sham; Jonathan Mill; Robin Murray; Marta Di Forti

doi:10.1038/s41380-024-02689-0

Methylomic signature of current cannabis use in two first-episode psychosis cohorts

Emma L. Dempster
, Chloe C.Y. Wong
, Joe Burrage
, Eilis Hannon
, Diego Quattrone
, Giulia Trotta
, Victoria Rodriguez
, Luis Alameda
, Edoardo Spinazzola
, Giada Tripoli
, Isabelle Austin-Zimmerman
, Zhikun Li
, Charlotte Gayer-Anderson
, Tom P. Freeman
, Emma C. Johnson
, Hannah E. Jongsma
, Simona Stilo
, Caterina La Cascia
, Laura Ferraro
, Daniele La Barbera

Antonio Lasalvia, Sarah Tosato, Ilaria Tarricone, Giuseppe D’Andrea, Michela Galatolo, Andrea Tortelli, Maurizio Pompili, Jean Paul Selten, Lieuwe de Haan, Paulo Rossi Menezes, Cristina M. Del Ben, Jose Luis Santos, Manuel Arrojo, Julio Bobes, Julio Sanjuán, Miguel Bernardo, Celso Arango, Peter B. Jones, Gerome Breen, Valeria Mondelli, Paola Dazzan, Conrad Iyegbe, Evangelos Vassos, Craig Morgan, Diptendu Mukherjee, Jim van Os, Bart Rutten, Michael C. O’Donovan, Pak Sham, Jonathan Mill, Robin Murray, Marta Di Forti

University of Exeter
King's College London
Washington University in St. Louis
Centre for Transcultural Psychiatry ‘Veldzicht’
ASP Crotone
Università di Palermo
University of Verona
Università di Bologna
51 Avenue de Maréchal de Lattre de Tassigny
Università degli Studi di Roma (Sapienza University of Rome)
Rivierduinen Institute for Mental Health Care
Vrije Universiteit Amsterdam
University of São Paulo
Hospital “Virgen de la Luz,”
USC University Hospital Complex (CHUS)
Universidad de Oviedo
University of Valencia
University of Barcelona
Universidad Complutense
University of Cambridge
Icahn School of Medicine at Mount Sinai
Maastricht University Medical Center
Wilhelmina Children's Hospital
MRC Centre for Neuropsychiatric Genetics and Genomics
Chinese University of Hong Kong
University of Hong Kong

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

5 Citations (SciVal)

Abstract

The rising prevalence and legalisation of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study aimed to explore the effects of current cannabis use and high-potency cannabis on DNA methylation in two independent cohorts of individuals experiencing first-episode psychosis (FEP) compared to control subjects. The combined sample consisted of 682 participants (188 current cannabis users and 494 never users). DNA methylation profiles were generated on blood-derived DNA samples using the Illumina DNA methylation array platform. A meta-analysis across cohorts identified one CpG site (cg11669285) in the CAVIN1 gene that showed differential methylation with current cannabis use, surpassing the array-wide significance threshold, and independent of the tobacco-related epigenetic signature. Furthermore, a CpG site localised in the MCU gene (cg11669285) achieved array-wide significance in an analysis of the effect of high-potency (THC = > 10%) current cannabis use. Pathway and regional analyses identified cannabis-related epigenetic variation proximal to genes linked to immune and mitochondrial function, both of which are known to be influenced by cannabinoids. Interestingly, a model including an interaction term between cannabis use and FEP status identified two sites that were significantly associated with current cannabis use with a nominally significant interaction suggesting that FEP status might moderate how cannabis use affects DNA methylation. Overall, these findings contribute to our understanding of the epigenetic impact of current cannabis use and highlight potential molecular pathways affected by cannabis exposure.

Original language	English
Article number	114
Pages (from-to)	1277-1286
Number of pages	10
Journal	Molecular Psychiatry
Volume	30
Issue number	4
Early online date	16 Oct 2024
DOIs	https://doi.org/10.1038/s41380-024-02689-0
Publication status	Published - 30 Apr 2025

Data Availability Statement

1. The datasets analysed during the current study are available in the GEO repository, The raw and processed data are available through GEO accession numbers GSE152027, and GSE152026. 2. Extended results tables for the EWAS analyses are available on the figShare repository https://doi.org/10.6084/m9.figshare.26003827.v1. 3. All data generated or analysed during this study are included in this published article [and its supplementary information files].

Acknowledgements

We thank all the contributors to the EU-GEI (WP2 group) study for their hard work: Kathryn Hubbard, Stephanie Beards, Simona A. Stilo, Mara Parellada, Pedro Cuadrado, José Juan Rodríguez Solano, Angel Carracedo, David Fraguas, Álvaro Andreu-Bernabeu, Gonzalo López, Bibiana Cabrera, Esther Lorente-Rovira, Paz Garcia-Portilla, Javier Costas, Estela Jiménez-López, Mario Matteis, Marta Rapado-Castro, Emiliano González, Covadonga M. Díaz-Caneja, Emilio Sánchez, Manuel Durán-Cutilla, Nathalie Franke, Fabian Termorshuizen, Daniella van Dam, Elsje van der Ven, Elles Messchaart, Marion Leboyer, Franck Schürhoff, Stéphane Jamain, Grégoire Baudin, Aziz Ferchiou, Baptiste Pignon, Jean-Romain Richard, Thomas Charpeaud, Anne-Marie Tronche, Flora Frijda, Giovanna Marrazzo, Crocettarachele Sartorio, Fabio Seminerio, Camila Marcelino Loureiro, Rosana Shuhama, Mirella Ruggeri, Chiara Bonetto, Doriana Cristofalo, Domnico Berardi, Marco Seri, Elena Bonora, Giuseppe D’Andrea, Laura Ferraro, Giada Tripoli, Silvia Amoretti, Gisela Mezquida.

Funding

This project was partialy funded by an MRC Senior Clinical Fellowship to MDF (MR/T007818/1). The lab\u00A0research was carried out at the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre (BRC). The authors acknowledge infrastructure funding from the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King\u2019s College London (NIHR203318). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. EU-GEI is the acronym of the project \u201CEuropean Network of National Schizophrenia Networks Studying Gene-Environment Interactions\u201D. The research leading to these results has received funding from the European Community\u2019s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (Project EU-GEI). We thank all the contributors to the EU-GEI (WP2 group) study for their hard work: Kathryn Hubbard, Stephanie Beards, Simona A. Stilo, Mara Parellada, Pedro Cuadrado, Jos\u00E9 Juan Rodr\u00EDguez Solano, Angel Carracedo, David Fraguas, \u00C1lvaro Andreu-Bernabeu, Gonzalo L\u00F3pez, Bibiana Cabrera, Esther Lorente-Rovira, Paz Garcia-Portilla, Javier Costas, Estela Jim\u00E9nez-L\u00F3pez, Mario Matteis, Marta Rapado-Castro, Emiliano Gonz\u00E1lez, Covadonga M. D\u00EDaz-Caneja, Emilio S\u00E1nchez, Manuel Dur\u00E1n-Cutilla, Nathalie Franke, Fabian Termorshuizen, Daniella van Dam, Elsje van der Ven, Elles Messchaart, Marion Leboyer, Franck Sch\u00FCrhoff, St\u00E9phane Jamain, Gr\u00E9goire Baudin, Aziz Ferchiou, Baptiste Pignon, Jean-Romain Richard, Thomas Charpeaud, Anne-Marie Tronche, Flora Frijda, Giovanna Marrazzo, Crocettarachele Sartorio, Fabio Seminerio, Camila Marcelino Loureiro, Rosana Shuhama, Mirella Ruggeri, Chiara Bonetto, Doriana Cristofalo, Domnico Berardi, Marco Seri, Elena Bonora, Giuseppe D\u2019Andrea, Laura Ferraro, Giada Tripoli, Silvia Amoretti, Gisela Mezquida. This project was partialy funded by an MRC Senior Clinical Fellowship to MDF (MR/T007818/1). The lab research was carried out at the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre (BRC) . The authors acknowledge infrastructure funding from the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King\u2019s College London (NIHR203318). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. EU-GEI is the acronym of the project \u201CEuropean Network of National Schizophrenia Networks Studying Gene-Environment Interactions\u201D. The research leading to these results has received funding from the European Community\u2019s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (Project EU-GEI) . We thank all the contributors to the EU-GEI (WP2 group) study for their hard work: Kathryn Hubbard, Stephanie Beards, Simona A. Stilo, Mara Parellada, Pedro Cuadrado, Jos\u00E9 Juan Rodr\u00EDguez Solano, Angel Carracedo, David Fraguas, \u00C1lvaro Andreu-Bernabeu, Gonzalo L\u00F3pez, Bibiana Cabrera, Esther Lorente-Rovira, Paz Garcia-Portilla, Javier Costas, Estela Jim\u00E9nez-L\u00F3pez, Mario Matteis, Marta Rapado-Castro, Emiliano Gonz\u00E1lez, Covadonga M. D\u00EDaz-Caneja, Emilio S\u00E1nchez, Manuel Dur\u00E1n-Cutilla, Nathalie Franke, Fabian Termorshuizen, Daniella van Dam, Elsje van der Ven, Elles Messchaart, Marion Leboyer, Franck Sch\u00FCrhoff, St\u00E9phane Jamain, Gr\u00E9goire Baudin, Aziz Ferchiou, Baptiste Pignon, Jean-Romain Richard, Thomas Charpeaud, Anne-Marie Tronche, Flora Frijda, Giovanna Marrazzo, Crocettarachele Sartorio, Fabio Seminerio, Camila Marcelino Loureiro, Rosana Shuhama, Mirella Ruggeri, Chiara Bonetto, Doriana Cristofalo, Domnico Berardi, Marco Seri, Elena Bonora, Giuseppe D\u2019Andrea, Laura Ferraro, Giada Tripoli, Silvia Amoretti, Gisela Mezquida.

Funders	Funder number
NIHR Imperial Biomedical Research Centre
EU-GEI
National Institute for Health and Care Research
NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust
NIHR Leicester Biomedical Research Centre
Angel Carracedo
José Juan Rodríguez Solano
European Commission	241909
Medical Research Council	MR/T007818/1
King's College London	NIHR203318
European Community's Seventh Framework Programme	HEALTH-F2-2010-241909

UN SDGs

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

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1038/s41380-024-02689-0Licence: CC BY

Cite this

Dempster, E. L., Wong, C. C. Y., Burrage, J., Hannon, E., Quattrone, D., Trotta, G., Rodriguez, V., Alameda, L., Spinazzola, E., Tripoli, G., Austin-Zimmerman, I., Li, Z., Gayer-Anderson, C., Freeman, T. P., Johnson, E. C., Jongsma, H. E., Stilo, S., La Cascia, C., Ferraro, L., ... Di Forti, M. (2025). Methylomic signature of current cannabis use in two first-episode psychosis cohorts. Molecular Psychiatry, 30(4), 1277-1286. Article 114. https://doi.org/10.1038/s41380-024-02689-0

Dempster, EL, Wong, CCY, Burrage, J, Hannon, E, Quattrone, D, Trotta, G, Rodriguez, V, Alameda, L, Spinazzola, E, Tripoli, G, Austin-Zimmerman, I, Li, Z, Gayer-Anderson, C, Freeman, TP, Johnson, EC, Jongsma, HE, Stilo, S, La Cascia, C, Ferraro, L, La Barbera, D, Lasalvia, A, Tosato, S, Tarricone, I, D’Andrea, G, Galatolo, M, Tortelli, A, Pompili, M, Selten, JP, de Haan, L, Menezes, PR, Del Ben, CM, Santos, JL, Arrojo, M, Bobes, J, Sanjuán, J, Bernardo, M, Arango, C, Jones, PB, Breen, G, Mondelli, V, Dazzan, P, Iyegbe, C, Vassos, E, Morgan, C, Mukherjee, D, van Os, J, Rutten, B, O’Donovan, MC, Sham, P, Mill, J, Murray, R & Di Forti, M 2025, 'Methylomic signature of current cannabis use in two first-episode psychosis cohorts', Molecular Psychiatry, vol. 30, no. 4, 114, pp. 1277-1286. https://doi.org/10.1038/s41380-024-02689-0

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title = "Methylomic signature of current cannabis use in two first-episode psychosis cohorts",

abstract = "The rising prevalence and legalisation of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study aimed to explore the effects of current cannabis use and high-potency cannabis on DNA methylation in two independent cohorts of individuals experiencing first-episode psychosis (FEP) compared to control subjects. The combined sample consisted of 682 participants (188 current cannabis users and 494 never users). DNA methylation profiles were generated on blood-derived DNA samples using the Illumina DNA methylation array platform. A meta-analysis across cohorts identified one CpG site (cg11669285) in the CAVIN1 gene that showed differential methylation with current cannabis use, surpassing the array-wide significance threshold, and independent of the tobacco-related epigenetic signature. Furthermore, a CpG site localised in the MCU gene (cg11669285) achieved array-wide significance in an analysis of the effect of high-potency (THC = > 10\%) current cannabis use. Pathway and regional analyses identified cannabis-related epigenetic variation proximal to genes linked to immune and mitochondrial function, both of which are known to be influenced by cannabinoids. Interestingly, a model including an interaction term between cannabis use and FEP status identified two sites that were significantly associated with current cannabis use with a nominally significant interaction suggesting that FEP status might moderate how cannabis use affects DNA methylation. Overall, these findings contribute to our understanding of the epigenetic impact of current cannabis use and highlight potential molecular pathways affected by cannabis exposure.",

author = "Dempster, \{Emma L.\} and Wong, \{Chloe C.Y.\} and Joe Burrage and Eilis Hannon and Diego Quattrone and Giulia Trotta and Victoria Rodriguez and Luis Alameda and Edoardo Spinazzola and Giada Tripoli and Isabelle Austin-Zimmerman and Zhikun Li and Charlotte Gayer-Anderson and Freeman, \{Tom P.\} and Johnson, \{Emma C.\} and Jongsma, \{Hannah E.\} and Simona Stilo and \{La Cascia\}, Caterina and Laura Ferraro and \{La Barbera\}, Daniele and Antonio Lasalvia and Sarah Tosato and Ilaria Tarricone and Giuseppe D{\textquoteright}Andrea and Michela Galatolo and Andrea Tortelli and Maurizio Pompili and Selten, \{Jean Paul\} and \{de Haan\}, Lieuwe and Menezes, \{Paulo Rossi\} and \{Del Ben\}, \{Cristina M.\} and Santos, \{Jose Luis\} and Manuel Arrojo and Julio Bobes and Julio Sanju{\'a}n and Miguel Bernardo and Celso Arango and Jones, \{Peter B.\} and Gerome Breen and Valeria Mondelli and Paola Dazzan and Conrad Iyegbe and Evangelos Vassos and Craig Morgan and Diptendu Mukherjee and \{van Os\}, Jim and Bart Rutten and O{\textquoteright}Donovan, \{Michael C.\} and Pak Sham and Jonathan Mill and Robin Murray and \{Di Forti\}, Marta",

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AU - Quattrone, Diego

AU - Trotta, Giulia

AU - Rodriguez, Victoria

AU - Alameda, Luis

AU - Spinazzola, Edoardo

AU - Tripoli, Giada

AU - Austin-Zimmerman, Isabelle

AU - Li, Zhikun

AU - Gayer-Anderson, Charlotte

AU - Freeman, Tom P.

AU - Johnson, Emma C.

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AU - Ferraro, Laura

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AU - Lasalvia, Antonio

AU - Tosato, Sarah

AU - Tarricone, Ilaria

AU - D’Andrea, Giuseppe

AU - Galatolo, Michela

AU - Tortelli, Andrea

AU - Pompili, Maurizio

AU - Selten, Jean Paul

AU - de Haan, Lieuwe

AU - Menezes, Paulo Rossi

AU - Del Ben, Cristina M.

AU - Santos, Jose Luis

AU - Arrojo, Manuel

AU - Bobes, Julio

AU - Sanjuán, Julio

AU - Bernardo, Miguel

AU - Arango, Celso

AU - Jones, Peter B.

AU - Breen, Gerome

AU - Mondelli, Valeria

AU - Dazzan, Paola

AU - Iyegbe, Conrad

AU - Vassos, Evangelos

AU - Morgan, Craig

AU - Mukherjee, Diptendu

AU - van Os, Jim

AU - Rutten, Bart

AU - O’Donovan, Michael C.

AU - Sham, Pak

AU - Mill, Jonathan

AU - Murray, Robin

AU - Di Forti, Marta

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AB - The rising prevalence and legalisation of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study aimed to explore the effects of current cannabis use and high-potency cannabis on DNA methylation in two independent cohorts of individuals experiencing first-episode psychosis (FEP) compared to control subjects. The combined sample consisted of 682 participants (188 current cannabis users and 494 never users). DNA methylation profiles were generated on blood-derived DNA samples using the Illumina DNA methylation array platform. A meta-analysis across cohorts identified one CpG site (cg11669285) in the CAVIN1 gene that showed differential methylation with current cannabis use, surpassing the array-wide significance threshold, and independent of the tobacco-related epigenetic signature. Furthermore, a CpG site localised in the MCU gene (cg11669285) achieved array-wide significance in an analysis of the effect of high-potency (THC = > 10%) current cannabis use. Pathway and regional analyses identified cannabis-related epigenetic variation proximal to genes linked to immune and mitochondrial function, both of which are known to be influenced by cannabinoids. Interestingly, a model including an interaction term between cannabis use and FEP status identified two sites that were significantly associated with current cannabis use with a nominally significant interaction suggesting that FEP status might moderate how cannabis use affects DNA methylation. Overall, these findings contribute to our understanding of the epigenetic impact of current cannabis use and highlight potential molecular pathways affected by cannabis exposure.

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Methylomic signature of current cannabis use in two first-episode psychosis cohorts

Abstract

Data Availability Statement

Acknowledgements

Funding

UN SDGs

ASJC Scopus subject areas

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