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Exploring the mediation of DNA methylation across the epigenome between childhood adversity and First Episode of Psychosis—findings from the EU-GEI study

Molecular Psychiatry volume 28, pages 2095–2106 (2023)Cite this article

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Studies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Adversity scores were created for abuse, neglect and composite adversity with the Childhood Trauma Questionnaire (CTQ). Regressions examining (I) CTQ scores with psychosis; (II) with DNAm EWAS level and (III) between DNAm and caseness, adjusted for a variety of confounders were conducted. Divide-Aggregate Composite-null Test for the composite null-hypothesis of no mediation effect was conducted. Enrichment analyses were conducted with missMethyl package and the KEGG database. Our results show that CA was associated with psychosis (Composite: OR = 1.68; p = <0.001; abuse: OR = 2.16; p < 0.001; neglect: OR = 2.27; p = <0.001). None of the CpG sites significantly mediated the adversity-psychosis association after Bonferroni correction (p < 8.1 × 10−8). However, 28, 34 and 29 differentially methylated probes associated with 21, 27, 20 genes passed a less stringent discovery threshold (p < 5 × 10−5) for composite, abuse and neglect respectively, with a lack of overlap between abuse and neglect. These included genes previously associated to psychosis in EWAS studies, such as PANK1, SPEG TBKBP1, TSNARE1 or H2R. Downstream gene ontology analyses did not reveal any biological pathways that survived false discovery rate correction. Although at a non-significant level, DNAm changes in genes previously associated with schizophrenia in EWAS studies may mediate the CA-psychosis association. These results and associated involved processes such as mitochondrial or histaminergic disfunction, immunity or neural signalling requires replication in well powered samples. The lack of overlap between mediating genes associated with abuse and neglect suggests differential biological trajectories linking CA subtypes and psychosis.

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Fig. 1: Interpreting the output of mediation analyses.
Fig. 2: Manhattan plot showing the DNAm mediating DMP between composite cumulative measure of adversity and psychosis.
Fig. 3: Diagram showing the mediating overlapping genes between composite, abuse and neglect analyses with psychosis.

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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. We thank strongly thank Romayne Gadelrab for her help with Fig. 3. We thank our funding bodies; The EU-GEI Project is funded by the European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (Project EU-GEI); Craig Morgan is part funded by the ESRC (ESRC Centre for Society and Mental Health at King’s College London: ESRC Reference: ES/S012567/1), and the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.

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Authors and Affiliations

  1. Service of General Psychiatry, Treatment and Early Intervention in Psychosis Program, Lausanne University Hospital (CHUV), Lausanne, Switzerland

    Luis Alameda

  2. Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience. King’s College of London, London, UK

    Luis Alameda, Victoria Rodriguez, Jim van Os, Atheeshaan Arumuham & Robin M. Murray

  3. Instituto de Investigación Sanitaria de Sevilla, IbiS, Hospital Universitario Virgen del Rocío, Department of Psychiatry, Universidad de Sevilla, Seville, Spain

    Luis Alameda

  4. Department of Biostatistics, Columbia University, New York, NY, USA

    Zhonghua Liu

  5. Department of Psychiatry, State Key Laboratory of Brain and Cognitive Sciences, and Centre for PanorOmic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong

    Pak C. Sham

  6. Social, Genetics and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Monica Aas, Giulia Trotta, Marta Di Forti, Radhika Kandaswamy, Diego Quattrone & Chloe C. Y. Wong

  7. Department of Mental Health and Addiction Services, ASP Crotone, Crotone, Italy

    Simona A. Stilo

  8. Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, Madrid, Spain

    Celso Arango

  9. Department of Psychiatry, Psychiatric Genetic Group, Instituto de Investigación Sanitaria de Santiago de Compostela, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago, Spain

    Manuel Arrojo

  10. Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi I Sunyer, Biomedical Research Networking Centre in Mental Health (CIBERSAM), Barcelona, Spain

    Miguel Bernardo

  11. Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain

    Julio Bobes

  12. Department of Medicine, Psychiatry Area, School of Medicine, Universidad de Oviedo, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Oviedo, Spain

    Julio Bobes

  13. Department of Psychiatry, Early Psychosis Section, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Lieuwe de Haan

  14. Neuroscience and Behaviour Department, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil

    Cristina Marta Del-Ben

  15. ESRC Centre for Society and Mental Health, King’s College London, London, UK

    Charlotte Gayer-Anderson & Craig Morgan

  16. LUMSA University, Department of Human Science and Department of Psychosis Studies, KCL, Rome, Italy

    Lucia Sideli

  17. Department of Psychiatry, University of Cambridge, Cambridge, UK

    Peter B. Jones

  18. CAMEO Early Intervention Service, Cambridgeshire & Peterborough NHS Foundation Trust, Cambridge, UK

    Peter B. Jones

  19. Psylife Group, Division of Psychiatry, University College London, London, UK

    Hannah E. Jongsma & James B. Kirkbride

  20. Section of Psychiatry, Department of Biomedicine, Neuroscience and advanced Diagnostic (BiND), University of Palermo, Palermo, Italy

    Caterina La Cascia

  21. Section of Psychiatry, Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy

    Antonio Lasalvia & Sarah Tosato

  22. Université Clermont Auvergne, Clermont-Ferrand, France

    Pierre-Michel Llorca

  23. Department of Preventive Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

    Paulo Rossi Menezes

  24. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, South Limburg Mental Health Research and Teaching Network, Maastricht University Medical Centre, Maastricht, The Netherlands

    Jim van Os, Bart P. Rutten & Jean-Paul Selten

  25. Department Psychiatry, Brain Centre Rudolf Magnus, Utrecht University Medical Centre, Utrecht, The Netherlands

    Jim van Os

  26. Department of Psychiatry, Servicio de Psiquiatría Hos“ital “Virgen de”a Luz”, C/Hermandad de Donantes de Sangre, 16002, Cuenca, Spain

    Jose Luis Santos

  27. Department of Psychiatry, School of Medicine, Universidad de Valencia, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), C/Avda. Blasco Ibáñez 15, 46010, Valencia, Spain

    Julio Sanjuán

  28. Rivierduinen Institute for Mental Health Care, Leiden, The Netherlands

    Jean-Paul Selten

  29. University of Paris Est Creteil, INSERM, IMRB, AP-HP, Hôpitaux Universitaires, H. Mondor, DMU IMPACT, Creteil, France

    Andrei Szöke

  30. Bologna Transcultural Psychosomatic Team (BoTPT), Department of Medical and Surgical Science, Alma Mater Studiorum Università di Bologna, Bologna, Italy

    Ilaria Tarricone

  31. Institute Mondor de recherché biomedicale, Creteil, France

    Andrea Tortelli

  32. GGZ (Mental Health Services) Noord Holland Noord, Heerhugowaard, the Netherlands

    Eva Velthorst

  33. Department of Psychiatry, Center for Psychiatric Neuroscience, Lausanne University Hospital (CHUV), Lausanne, Switzerland

    Emma Dempster, Eilis Hannon, Joe Burrage & Jonathan Mill

  34. Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK

    Daniella Dwir

  35. Psychiatric Imaging Group, MRC London Institute of Medical Sciences, London, UK

    Atheeshaan Arumuham

  36. South London and Maudsley NHS Foundation Trust, London, UK

    Atheeshaan Arumuham

  37. Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK

    Atheeshaan Arumuham

Authors
  1. Luis Alameda
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  2. Zhonghua Liu
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  3. Pak C. Sham
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  4. Monica Aas
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  5. Giulia Trotta
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  6. Victoria Rodriguez
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  7. Marta Di Forti
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  8. Simona A. Stilo
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  9. Radhika Kandaswamy
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  10. Celso Arango
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  11. Manuel Arrojo
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  13. Julio Bobes
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  14. Lieuwe de Haan
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  15. Cristina Marta Del-Ben
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  16. Charlotte Gayer-Anderson
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  34. Andrea Tortelli
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  35. Eva Velthorst
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  36. Craig Morgan
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  37. Emma Dempster
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  38. Eilis Hannon
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  39. Joe Burrage
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  40. Daniella Dwir
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  41. Atheeshaan Arumuham
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  42. Jonathan Mill
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  43. Robin M. Murray
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  44. Chloe C. Y. Wong
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Contributions

LA conceptualised and designed the study, conducted the statistical analyses and wrote the initial draft; CW and RM conceptualised and designed the study; reviewed the initial draft and supervised the project; LZ created the DACT and conducted statistical analyses and reviewed the initial draft; PCS, MDF contributed to the design and reviewed the initial draft; MA, GT, VR, SAS, RK, CA, MA, MB, JB, LDH, CMD, CGA, LS, PBJ, HEJ, JBK, CLC, AL, ST, PML, PRM, JVO, BPR, JLS, JS, JPS, AS, IT, AT, EV, CM, ED reviewed the first draft and contributed to data collection and EUGEI planning, DD, AA reviewed the first draft, JM, EH, JB, ED reviewed the first draft and contributed to data collection and preparation; DQ data management.

Corresponding author

Correspondence to Luis Alameda.

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Competing interests

MB has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of AB-Biotics, Adamed, Angelini, Casen Recordati, Janssen-Cilag, Menarini, Rovi and Takeda. CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. PBJ declare to have consulted for Ricordati and Janssen. RM has received payments for non-promotional seminars from JANSSEN, SUNOVIAN, LUNDBECK AND OTSUKA.

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Alameda, L., Liu, Z., Sham, P.C. et al. Exploring the mediation of DNA methylation across the epigenome between childhood adversity and First Episode of Psychosis—findings from the EU-GEI study. Mol Psychiatry 28, 2095–2106 (2023). https://doi.org/10.1038/s41380-023-02044-9

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