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.