Longitudinal DNA methylation dynamics distinguish persistent and remitted attention-deficit/hyperactivity disorder in childhood and adolescence.

BACKGROUND

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.

METHODS

We analyzed 219 saliva samples from 94 participants (aged 9.5-14.5 years) attending two to three waves of NICAP (Neuroimaging of the Children's Attention Project). 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) individuals with versus without ADHD, (2) persistent or remitted ADHD versus without ADHD, and (3) persistent versus remitted ADHD. False discovery rate correction controlled for multiple testing (FDR-adjusted-p < 0.05).

RESULTS

Comparison (1) showed null findings after correction for multiple testing. In contrast to those without ADHD (2), the average DNAm was statistically different at 2 sites in persistent ADHD (FDR-adjusted-p < 0.05) and 3 sites in remitted ADHD (FDR-adjusted-p < 0.03), and methylation of 3 additional CpGs differentially changed in persistent ADHD (FDR-adjusted-p < 0.04). Remitted differed from persistent ADHD (3) at 4 CpGs, including cg21443143 (ZFAT), which showed a decline over time. Gene enrichment links findings to brain structures and function, though these did not survive multiple testing.

CONCLUSIONS

Our 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.