Longitudinal associations of DNA methylation and sleep in children: a meta-analysis

Abstract

Background Sleep is important for healthy functioning in children. Numerous genetic and environmental factors, from conception onwards, may influence this phenotype. Epigenetic mechanisms such as DNA methylation have been proposed to underlie variation in sleep or may be an early-life marker of sleep disturbances. We examined if DNA methylation at birth or in school age is associated with parent-reported and actigraphy-estimated sleep outcomes in children. Methods We meta-analysed epigenome-wide association study results. DNA methylation was measured from cord blood at birth in 11 cohorts and from peripheral blood in children (4–13 years) in 8 cohorts. Outcomes included parent-reported sleep duration, sleep initiation and fragmentation problems, and actigraphy-estimated sleep duration, sleep onset latency and wake-after-sleep-onset duration. Results We found no associations between DNA methylation at birth and parent-reported sleep duration (n = 3658), initiation problems (n = 2504), or fragmentation (n = 1681) (p values above cut-off 4.0 × 10–8). Lower methylation at cg24815001 and cg02753354 at birth was associated with longer actigraphy-estimated sleep duration (p = 3.31 × 10–8, n = 577) and sleep onset latency (p = 8.8 × 10–9, n = 580), respectively. DNA methylation in childhood was not cross-sectionally associated with any sleep outcomes (n = 716–2539). Conclusion DNA methylation, at birth or in childhood, was not associated with parent-reported sleep. Associations observed with objectively measured sleep outcomes could be studied further if additional data sets become available.

Epigenetics applied to child and adolescent mental health: Progress, challenges and opportunities

“…The most notable example is ST3GAL3: common variation in this gene has also been identified as a top GWAS hit for ADHD (Demontis et al, 2019;Klein et al, 2019), rare mutations of ST3GAL3 associate with cognitive and motor developmental delays (Khamirani et al, 2021), and ST3GAL3 knockout in mice results in profound cognitive deficits and hyperactivity due to myelination disruption (Rivero et al, 2021). Similar epigenetic timing effects (i.e., where prospective associations at birth show overall a stronger signal in EWAS results than cross-sectional associations in childhood) have also been observed for other neurodevelopmental phenotypes (e.g., social communication deficits (Rijlaarsdam et al, 2021)), but not for broader child mental (e.g., general psychopathology (Rijlaarsdam et al, 2022), sleep problems (Sammallahti et al, 2022)) or physical (e.g., BMI; Vehmeijer et al, 2020) health outcomes, despite studies using largely overlapping data, which points to a degree of phenotypic specificity. A detailed overview of epigenetic timing effects in the context of neurodevelopmental conditions such as ADHD, outstanding questions and research priorities in this area can be found elsewhere (Cecil & Nigg, 2022).…”

“…where prospective associations at birth show overall a stronger signal in EWAS results than cross-sectional associations in childhood) have also been observed for other neurodevelopmental phenotypes (e.g., social communication deficits (Rijlaarsdam et al, 2021)), but not for broader child mental (e.g., general psychopathology (Rijlaarsdam et al, 2022), sleep problems (Sammallahti et al, 2022)) or physical (e.g., BMI; Vehmeijer et al, 2020) health outcomes, despite studies using largely overlapping data, which points to a degree of phenotypic specificity. A detailed overview of epigenetic timing effects in the context of neurodevelopmental conditions such as ADHD, outstanding questions and research priorities in this area can be found elsewhere (Cecil & Nigg, 2022).…”

Potential genetic and epigenetic mechanisms in insomnia: A systematic review

“…Currently, research has proposed that DNA methylation may also serve as a mechanism by which genetic and environmental exposures influence sleep, mediating the effect of stressors on sleep and the circadian system (Qureshi et al, 2014). DNA methylation has been associated with up‐regulation of the hypothalamic–pituitary–adrenal (HPA) axis and it has been considered an early‐life marker of sleep disturbances (Nakahara et al, 2021; Sammallahti et al, 2022). DNA methylation is also an important mediator of environmental factors and regulators of circadian rhythms; hence, the epigenetic system may be the key factor in neuropsychiatric disorders including sleep disturbances (Qureshi & Mehler, 2014; Liu & Chung, 2015).…”

Epigenetic timing effects on child developmental outcomes: A longitudinal meta-regression of findings from the Pregnancy And Childhood Epigenetics Consortium

“…The Erasmus MC Medical Ethics Review Committee and respective local ethics committees previously approved the included studies. [7][8][9]17,18 EWAS summary statistics included the association between DNAm (predictor) and a phenotype (outcome). DNAm was either measured in cord blood at birth or in peripheral blood in childhood with either Illumina 450K or EPIC arrays (although only 450K DNAm sites remained after QC, see below).…”

“…14 However, it is challenging to fully separate the influence of tissue versus timing, as for example cord blood is only available at birth, and early cell-type changes are in part developmentally regulated. 14,15 Recently, the Pregnancy And Childhood Epigenetics (PACE) Consortium 16 published five multi-cohort EWAS meta-analyses that investigated DNAm using both designs in relation to the same child outcome, spanning mental and physical health domains, namely: ADHD, 8 general psychopathology (measured as a latent factor; GPF), 17 sleep duration, 18 body mass index (BMI) 9 and asthma 7 . Results from these previous studies can be summarized as follows (Table 1): for ADHD, there were more hits for DNAm at birth rather than in childhood (i.e prospective EWAS showed more hits than cross-sectional EWAS); whereas the opposite was true for BMI and asthma (i.e.…”