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Epigenetic profiling of ADHD symptoms trajectories: a prospective, methylome-wide study

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Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent developmental disorder, associated with a range of long-term impairments. Variation in DNA methylation, an epigenetic mechanism, is implicated in both neurobiological functioning and psychiatric health. However, the potential role of DNA methylation in ADHD symptoms is currently unclear. In this study, we examined data from the Avon Longitudinal Study of Parents and Children (ALSPAC)—specifically the subsample forming the Accessible Resource for Integrated Epigenomics Studies (ARIES)—that includes (1) peripheral measures of DNA methylation (Illumina 450k) at birth (n=817, 49% male) and age 7 (n=892, 50% male) and (2) trajectories of ADHD symptoms (7–15 years). We first employed a genome-wide analysis to test whether DNA methylation at birth associates with later ADHD trajectories; and then followed up at age 7 to investigate the stability of associations across early childhood. We found that DNA methylation at birth differentiated ADHD trajectories across multiple genomic locations, including probes annotated to SKI (involved in neural tube development), ZNF544 (previously implicated in ADHD), ST3GAL3 (linked to intellectual disability) and PEX2 (related to perixosomal processes). None of these probes maintained an association with ADHD trajectories at age 7. Findings lend novel insights into the epigenetic landscape of ADHD symptoms, highlighting the potential importance of DNA methylation variation in genes related to neurodevelopmental and peroxisomal processes that play a key role in the maturation and stability of cortical circuits.

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Acknowledgements

We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, including interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. With regard to the ALSPAC DNA methylation, we thank all involved, particularly the laboratory scientists and bioinformaticians, who contributed considerable time and expertise to the data in this paper. The UK Medical Research Council and the Wellcome Trust (Grant Ref: 092731 to ED Barker and J Mill) and the University of Bristol provide core support for ALSPAC. This work was funded by the National Institute of Child and Human Development Grant (R01HD068437). ARIES was funded by the BBSRC (BBI025751/1 and BB/I025263/1). ARIES is maintained under the auspices of the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/2 and MC_UU_12013/8). Dr Walton is supported by the German Research Foundation. Dr Pingault is supported by a European Commission Marie Curie Intra-European Fellowship (No. 330699). Dr Cecil is supported by the Economic and Social Research Council (Grant Ref: ES/N001273/1).

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Walton, E., Pingault, JB., Cecil, C. et al. Epigenetic profiling of ADHD symptoms trajectories: a prospective, methylome-wide study. Mol Psychiatry 22, 250–256 (2017). https://doi.org/10.1038/mp.2016.85

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