Sleep timing and duration in relation to blood leukocyte DNA methylation in adolescents: an epigenome-wide analysis

To investigate associations between adolescent sleep duration and timing, and blood leukocyte DNA methylation, one type of epigenetic modification that may respond to changes in sleep. Cross-sectional epigenome-wide analysis of DNA methylation was conducted to identify sleep-related CpG sites in 269 females and 233 males (14.4±2.1 years on average) from the ELEMENT cohort study, in Mexico City. Sleep duration and midpoint on weekdays and weekends were assessed using 7-day wrist actigraphy (Actigraph GTX-BT), and DNA methylation in blood leukocytes was measured using the Illumina Infinium Methylation EPIC BeadChip. Linear regression was conducted to assess the relationship between sleep variables and DNA methylation at each array locus, adjusting for demographic confounders, batch effects, and cell types. Differentially methylated regions (DMRs) were assessed using ipDMR, and subsequent pathway analysis of relevant genes was conducted. At false discovery rate-adjusted p-value (Q)<0.05, there was one inverse site-specific association between sleep midpoint on weekends and cg04070324 (not annotated to a specific gene) among males only (Q=0.02). However, DMR analysis in the full sample revealed 1875 total significant DMRs at Q<0.05, and there was little overlap of DMRs associated with sleep duration versus midpoint. Sex-stratified analysis revealed more associations among males than females (e.g., 3284 DMRs compared to 1346). Based on pathway enrichment analysis, the male-specific pathways for sleep duration were related to DNA and metabolism, whereas for sleep midpoint they were related to developmental processes. Epigenome-wide analysis identified distinct associations with sleep duration and timing, especially among male adolescents.