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DNA methylation and general psychopathology in childhood: an epigenome-wide meta-analysis from the PACE consortium

Abstract

The general psychopathology factor (GPF) has been proposed as a way to capture variance shared between psychiatric symptoms. Despite a growing body of evidence showing both genetic and environmental influences on GPF, the biological mechanisms underlying these influences remain unclear. In the current study, we conducted epigenome-wide meta-analyses to identify both probe- and region-level associations of DNA methylation (DNAm) with school-age general psychopathology in six cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. DNAm was examined both at birth (cord blood; prospective analysis) and during school-age (peripheral whole blood; cross-sectional analysis) in total samples of N = 2178 and N = 2190, respectively. At school-age, we identified one probe (cg11945228) located in the Bromodomain-containing protein 2 gene (BRD2) that negatively associated with GPF (p = 8.58 × 10–8). We also identified a significant differentially methylated region (DMR) at school-age (p = 1.63 × 10–8), implicating the SHC Adaptor Protein 4 (SHC4) gene and the EP300-interacting inhibitor of differentiation 1 (EID1) gene that have been previously implicated in multiple types of psychiatric disorders in adulthood, including obsessive compulsive disorder, schizophrenia, and major depressive disorder. In contrast, no prospective associations were identified with DNAm at birth. Taken together, results of this study revealed some evidence of an association between DNAm at school-age and GPF. Future research with larger samples is needed to further assess DNAm variation associated with GPF.

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Fig. 1: Quantile-quantile plot of the meta-analytic associations of DNA methylation at birth and DNA methylation at school-age with general psychopathology.
Fig. 2: Manhattan plot of –log10 p-values versus CpG position (base pair and chromosome) showing meta-analytic associations of DNA methylation at birth and DNA methylation at school-age with general psychopathology.

Data availability

Site-level meta-analytical results will be made publicly available (Supplementary data file) upon acceptance for publication. For access to cohort-level data, requests can be sent directly to individual studies.

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Contributions

JR: analysis plan and study design, Generation R analysis, quality control of data and meta-analyses, interpretation of results, manuscript drafting; MCT: Helix and INMA analyses, quality control of data, shadow meta-analysis, functional and genomic enrichment analyses, results interpretation, manuscript drafting, revision; LS: contributed to analysis plan and study design, ALSPAC analysis, interpretation of results, and manuscript review; SaA: DCHS analysis, and manuscript review; AM: GLAKU analysis and manuscript review; AN: Generation R coordination, manuscript review; JF: study design, Generation R coordination, critical revision of the manuscript; JS: INMA coordination, provided funding, manuscript review; KBG: MoBa Helix funding, MoBa coordination; RG: KANC-Helix funding, KANC coordination; JW: BiB-Helix funding, BiB coordination; MK: Rhea-Helix data acquisition; HJZ: DCHS coordination, and manuscript review; DJS: DCHS coordination, and manuscript review; KH: GLAKU coordination, manuscript review; KR: GLAKU coordination, manuscript review; JL: GLAKU coordination, manuscript review; AH: DCHS analysis, and manuscript review; DC: contributed to analysis plan and review of drafts and manuscript; SiA: analysis plan and study design, INMA analysis, manuscript review; CC: analysis plan and study design, Generation R coordination, funding, manuscript drafting and review.

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Correspondence to Marta Cosin-Tomas or Charlotte A. M. Cecil.

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Rijlaarsdam, J., Cosin-Tomas, M., Schellhas, L. et al. DNA methylation and general psychopathology in childhood: an epigenome-wide meta-analysis from the PACE consortium. Mol Psychiatry 28, 1128–1136 (2023). https://doi.org/10.1038/s41380-022-01871-6

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