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Association between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis.

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Walton, Esther 
González, Juan Ramon  ORCID logo


Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4-15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p < 0.05) in either of the EWAS were correlated between timepoints (ρ = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p < 1 × 10-7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p < 1 × 10-7. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.


Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi:


Adolescent, Attention Deficit Disorder with Hyperactivity, Child, Child, Preschool, DNA Methylation, Epigenesis, Genetic, Female, Humans, Infant, Newborn, Pregnancy, Prospective Studies, Schools

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Transl Psychiatry

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Springer Science and Business Media LLC
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) (016.VICI.170.200, 024.001.003)
RCUK | Economic and Social Research Council (ESRC) (ES/S013229/1)
RCUK | Medical Research Council (MRC) (MC_UU_00011/5, MC_UU_00011/5, MR/S009310/1)
Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III) (MS14/00108, CP14/00108, MS13/00054, CP18/00018)