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

Luis Alameda, Zhonghua Liu, Pak Sham, Monica Aas, Giulia Trotta, Victoria Rodriguez, Marta Di Forti, Simona A. Stilo, Radhika Kandaswamy, Celso Arango, Manuel Arrojo, Miguel Bernardo, Julio Bobes, Lieuwe De Haan, Cristina Marta Del-Ben, Charlotte Gayer-Anderson, Lucia Sideli, Peter B Jones, Hannah E. Jongsma, James B KirkbrideCaterina La Cascia, Antonio Lasalvia, Sarah Tosato, Pierre-Michel Llorca, Paulo Rossi Menezes, Jim Van Os, Diego Quattrone, Bart P. F. Rutten, Jose Luis Santos, Julio Sanjuán, Jean Paul Selten, Andrei Szöke, Ilaria Tarricone, Eva Velthorst, Craig Morgan, Emma L. Dempster, Eilis Hannon, Joe Burrage, Daniella Dwir, Atheeshaan Arumuham, Jonathan Mill, Robin Murray, Chloe Wong

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2095-2106
Number of pages12
JournalMolecular Psychiatry
Volume28
Issue number5
DOIs
Publication statusPublished - 17 Apr 2023

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