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

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 In nium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Polyvictimization 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), then 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 = 3.09; p = <0.001; abuse: OR = 2.95; p<0.001; neglect: OR = 3.25; p=<0.001). None of the CpG sites signi cantly mediated the adversity-psychosis association after Bonferroni correction (p<8.1x10-8). However, 28, 34 and 29 differentially methylated probes associated with 21, 27, 20 genes passed a less stringent discovery threshold (p<5x10-5) for composite, abuse, and neglect respectively, with a lack of overlap between abuse and neglect. These included genes previously associated with 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-signi cant level, DNAm changes in genes previously associated with schizophrenia in EWAS studies may mediate the CApsychosis association. These results and associated involved processes such as mitochondrial or histaminergic dysfunction, immunity or neural signaling require replication in well-powered samples.Mediating genes were not associated with abuse and neglect, tentatively suggest differential biological trajectories linking CA subtypes and psychosis.

Aggregated epigenetic profiles explain the intergenerational transmission of physical neglect with psychiatric, cognitive, and bonding effects.

“…In our SEM model, EMNs was positively related to internalizing and externalizing symptoms and negatively to cognitive integrity, aligning with the neglect vulnerability pro le. DNAm has demonstrated susceptibility to psychiatric phenotypes in adults (12,20), and a single episode of psychosis (54). This connection between EMNs, psychopathological symptoms and poor cognitive integrity also aligns with longitudinal behavioral evidence indicating the impact of childhood neglect on cognitive function, educational outcomes in adolescence, and mental health problems, including anxiety, depression, PTSD, and psychosis in young adulthood (24).…”

Uncovering aggregated epigenetic index effects on intergenerational transmission of physical neglect and its psychiatric, cognitive, and bonding impact

“…In our SEM model, EMNs was positively related to internalizing and externalizing symptoms and negatively to cognitive integrity, in line with the neglect vulnerability pro le. DNAm has already shown underlying susceptibility to complex psychiatric phenotypes in adults (18, 19), and a single episode of psychosis (54). This relation of EMN to psychopathological symptoms and poor cognitive integrity also converged with longitudinal behavioral evidence showing the impact of childhood neglect on cognitive function and poor educational outcomes in adolescence, as well as mental health problems, including anxiety, depression, PTSD, and psychosis in young adulthood (22).…”

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

“…Genome-wide DNA methylation was pro led in the GAP cohort using the Illumina 450K DNA methylation array (Illumina Inc) which interrogates > 450,000 DNA methylation sites across the genome 29 . The EU-GEI cohort was analysed using the Illumina EPIC DNA methylation array (Illumina Inc), which interrogates > 850,000 DNA methylation sites across the genome 30 . After stringent data quality control (see below) the GAP dataset consisted of DNA methylation estimates for 430660 DNA methylation sites pro led in 225 samples (87 frequent cannabis users & 138 cannabis naive controls).…”