Abstract
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.
Highlights
Attention-deficit and hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by impulsivity, excessive activity, and attention problems.Symptoms often become apparent during school age with a world-wide prevalence of 5–7.5%1
We examined whether any CpG sites associated with ADHD symptoms are associated with prenatal maternal stress
The identified probes showed a pattern of a high average rate of methylation in cord blood, while lower levels of methylation were associated with more ADHD symptoms in childhood
Summary
Attention-deficit and hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by impulsivity, excessive activity, and attention problems. Symptoms often become apparent during school age with a world-wide prevalence of 5–7.5%1. Genetic heritability is estimated between 64 and 88%2,3. Several environmental factors are suspected to impact ADHD, Neumann et al Translational Psychiatry (2020)10:398 e.g., prenatal maternal smoking or lead exposure[4,5,6,7]. The genetics and environmental pathways contributing to ADHD risk remain unclear. DNA methylation, an epigenetic mechanism regulating gene expression, may mediate genetic or environmental effects
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