Wrigglesworth, J. | Search bioRxiv

bioRxiv2026

Genetic and environmental factors associated with DNA methylation across childhood and adolescence in individuals with and without attention-deficit/hyperactivity disorder

Background: Genetic and environmental factors both contribute risk to the development of childhood Attention-deficit/hyperactivity disorder (ADHD), yet the molecular mechanisms conferring this risk remain unclear. We investigated the genetic and environmental factors influencing DNA methylation (DNAm) at sites linked to ADHD symptom trajectories. Methods: We used two overlapping subsamples from a longitudinal paediatric cohort: (1) children with genetic and epigenetic data at first wave saliva sampling (Wave 3, n=113, 9.47-11.86 years) underwent methylation quantitative trait loci (meQTL) analysis; (2) children with environmental (Waves 1-3) and one or more waves of epigenetic data (n=126, 9.5-11.9 years) were analysed using LASSO regression to identify predictors of ADHD (Remitted ADHD/Persistent ADHD/Controls) and Wave 3 DNAm. In a subset with multiple DNAm timepoints (n=75), linear mixed models tested whether environmental predictors associated with longitudinal DNAm change, and whether ADHD moderated these associations. Analyses were conducted on 12 CpGs in which we previously identified change in DNAm according to the ADHD clinical outcome. Results: Nineteen meQTLs for 5 CpGs explained up to 40% of DNAm variance. We identified 17 environmental predictors of ADHD and wave 3 DNAm. Higher household income and school quality of life (QoL) were associated with reduced DNAm at cg02208776 (household) and cg11124426 (QoL) over time. Critically, higher income in Remitted ADHD showed greater DNAm declines than Controls, with opposite patterns in Persistent ADHD. Conclusion: DNAm patterns linked to ADHD outcomes were associated with genetic and environmental factors. Notably, household income and school functioning were associated with epigenetic change, with income effects varying by ADHD trajectories - characterising higher income as protective in remittent individuals.

genomics↗

bioRxiv2025

Longitudinal DNA methylation dynamics distinguish Persistent and Remitted ADHD in childhood and adolescence

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, with symptoms that remit or persist over time. Biological mechanisms underlying symptom change remain poorly understood, though epigenetic processes, like DNA methylation (DNAm), may serve as dynamic biomarkers of clinical outcomes. We examined change in DNAm in children and adolescents with and without ADHD, including differences between remitted and persistent ADHD. MethodsWe analyzed 219 saliva samples from 94 participants (aged 9.5-14.5 years) attending 2 to 3 waves of NICAP. DNAm was profiled using the Infinium MethylationEPIC BeadChip. Linear mixed models adjusted for age, sex, medication, batch and cell-proportion assessed longitudinal change. Comparisons included (1) all ADHD cases versus controls, (2) persistent or remitted ADHD versus controls, and (3) persistent versus remitted ADHD. False discovery rate correction controlled for multiple testing (FDR p<0.05). ResultsNo CpGs were statistically different between ADHD and controls, after correction. Compared to controls, the average DNAm at 5 sites was statistically different in persistent or remitted ADHD, and methylation of 3 additional CpGs differentially changed over time in persistent ADHD. Remitted differed from persistent ADHD at four CpGs, including cg21443143 (ZFAT), which showed a unique decline over time. Gene enrichment links findings to brain structures and function, though these did not survive multiple testing. ConclusionOur study identified several epigenetic differences between remitted and persistent ADHD outcomes from typical development, and from each other. Given the early stage of this research, our findings warrant further prospective epigenome-wide studies into these diagnostic trajectories.

genomics↗