Association between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis
2020
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.
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