Abtract
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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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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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.
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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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DOI: https://doi.org/10.1038/s41380-023-02044-9