Genome-wide DNA methylation patterns associated with sleep and mental health in children: a population-based study.

BACKGROUND: DNA methylation (DNAm) has been implicated in the biology of sleep. Yet, how DNAm patterns across the genome relate to different sleep outcomes, and whether these associations overlap with mental health is currently unknown. Here, we investigated associations of DNAm with sleep and mental health in a pediatric population. METHODS: This cross-sectional study included 465 10-year-old children (51.3% female) from the Generation R Study. Genome-wide DNAm levels were measured using the Illumina 450K array (peripheral blood). Sleep problems were assessed from self-report and mental health outcomes from maternal questionnaires. Wrist actigraphy was used in 188 11-year-old children to calculate sleep duration and midpoint sleep. Weighted gene co-expression network analysis was used to identify highly comethylated DNAm 'modules', which were tested for associations with sleep and mental health outcomes. RESULTS: We identified 64 DNAm modules, one of which associated with sleep duration after covariate and multiple testing adjustment. This module included CpG sites spanning 9 genes on chromosome 17, including MAPT - a key regulator of Tau proteins in the brain involved in neuronal function - as well as genes previously implicated in sleep duration. Follow-up analyses suggested that DNAm variation in this region is under considerable genetic control and shows strong blood-brain concordance. DNAm modules associated with sleep did not overlap with those associated with mental health. CONCLUSIONS: We identified one DNAm region associated with sleep duration, including genes previously reported by recent GWAS studies. Further research is warranted to examine the functional role of this region and its longitudinal association with sleep.

Childhood sleep disturbances and white matter microstructure in preadolescence.

BACKGROUND: Sleep problems occur in up to 30% of children and have been associated with adverse developmental outcomes. However, due to a lack of longitudinal neuroimaging studies, the neurobiological changes that may underlie some of these associations have remained unclear. This study explored the association between sleep problems during childhood and white matter (WM) microstructure in preadolescence. METHODS: Children from the population-based birth cohort, the Generation R Study, who had repeatedly assessed sleep problems between 1.5 and 10 years of age and a MRI scan at age 10 (N = 2,449), were included. Mothers reported on their child's sleep problems using the Child Behavior Checklist (CBCL 1.5-5) when children were 1.5, 3, and 6 years of age. At age 2, mothers completed very similar questions. At age 10, both children and their mothers reported on sleep problems. We used whole-brain and tract-specific fractional anisotropy (FA) and mean diffusivity (MD) values obtained through diffusion tensor imaging as measures of WM microstructure. RESULTS: Childhood sleep problems at 1.5, 2, and 6 years of age were associated with less WM microstructural integrity (approximately 0.05 SD lower global FA score per 1-SD sleep problems). In repeated-measures analyses, children with more sleep problems (per 1-SD) at baseline had lower FA values at age 10 in particular in the corticospinal tract (-0.12 SD, 95% CI:-0.20;-0.05), the uncinate fasciculus (-0.12 SD, 95% CI:-0.19;-0.05), and the forceps major (-0.11 SD, 95% CI:-0.18;-0.03), although effect estimates across the tracts did not differ substantially. CONCLUSIONS: Childhood sleep disturbances are associated with less WM microstructural integrity in preadolescence. Our results show that early neurodevelopment may be a period of particular vulnerability to sleep problems. This study cannot demonstrate causality but suggests that preventive interventions addressing sleep problems should be further explored to test whether they impact adverse neurodevelopment.

Preschool family irregularity and the development of sleep problems in childhood: a longitudinal study.

BACKGROUND: Previous studies have shown that poor family environments are related to more sleep problems; however, little is known about how family irregularity in early life affects the development of sleep problems over childhood using objective sleep measures. The current study tests the hypothesis that early family irregularity contributes to the development of sleep problems. METHODS: This population-based study comprises 5,443 children from the Generation R Study. Family irregularity was measured with seven maternal-reported questions on family routines when children were 2 and 4 years old. Mothers reported on sleep problems at child age 3, 6, and 10 years, whereas children completed questionnaires on sleep problems at age 10. Additionally, we used tri-axial wrist accelerometers for five nights in 851 children (mean age 11.7 years) to assess sleep objectively. RESULTS: Family irregularity was associated with more mother- and child-reported sleep problems at ages 3, 6, and 10 years as well as with a shorter sleep duration and later objective sleep onset, but not with sleep efficiency or waking time. The association between family irregularity and multi-informant subjective sleep problems at age 10 years was mediated by mother-reported child psychopathology at age 6 years. CONCLUSIONS: Our findings show a long-term robust association of preschool family irregularity with more sleep problems during childhood as well as shorter sleep duration and later sleep onset as measured objectively with actigraphy. In part, these sleep problems were associated with family irregularity by way of child psychopathology. These findings suggest that interventions improving preschool family irregularity, which are targeted to reduce child psychopathology, may also impact the development of sleep problems beneficially.

Classifying Pubertal Development Using Child and Parent Report: Comparing the Pubertal Development Scales to Tanner Staging.

PURPOSE: This project investigated internal consistency and test-retest reliability of the frequently used Pubertal Development Scale (PDS) and compared parent and child reports with clinician-rated Tanner staging. METHODS: Using a repository of data collected from 1995 to 2016, 252 participants (aged 7.8-17.7 years) provided self- and parent-reported PDS and received Tanner staging by a certified health care professional within 30 days. Internal consistency and test-retest reliability statistics were evaluated for 56 children across two assessments occurring within 6 months. Comparisons with Tanner staging involved examining concurrent validity and calibration analysis using data from 233 child and 252 parental ratings. RESULTS: Self- and parent-reported PDS demonstrated good internal consistency, with Cronbach's alpha .91-.96; high test-retest reliability was confirmed with intraclass correlation coefficient .81-.92. The association of Tanner stage with self- and parent-reported PDS was moderate to high; Kendall's Tau ranged from .67 to .76, and intraclass correlation coefficient ranged from .73 to 83. The absolute agreement of Tanner stage with self- and parent-reported PDS was low; Cohen's Kappa ranged from .20 to .37. However, combining pubertal scores into three stages of development (pre/early-, mid-, and late/post-pubertal) improved interrater agreement across measures (κ = .65, 95% confidence interval = .57-.73). CONCLUSIONS: The present study shows that the PDS is reliable and generally tracks with Tanner staging (for both self and parent report). Low absolute agreement indicates that PDS categories do not map directly to specific Tanner stages, partly because a premature adrenarche is often misinterpreted by parents and pediatricians alike. However, three broad categories showed better agreement and are generally adequate for most applications in child and adolescent research.