0031 Sleep Regularity is Associated with DNA Methylation in Cognitive, Cardiovascular and Mood-related Genes: A GWAS-informed Study in Adolescents

Abstract

Introduction Adolescence is associated with a delay in the circadian timing of sleep. However, social factors prevent adolescents from adapting to a later sleep-wake pattern, leading to different forms of circadian misalignment that may increase the risk of cardiovascular and mental health disorders. Several GWAS have identified genes associated with sleep and circadian phenotypes, however, little is known regarding the epigenetic basis and significance of sleep timing and its regularity in adolescence. Methods We analyzed data from 230 adolescents from the Penn State Child Cohort follow-up study who provided a blood sample for DNA extraction and had complete at-home 7-night (at least 3) actigraphy (ACT) data. ACT-measured sleep midpoint was calculated as the intra-individual mean of the 7-night midpoint (zeroed to midnight) of the sleep period. ACT-measured sleep regularity was calculated as the intra-individual standard deviation of the 7-night sleep midpoint. Epigenome-wide single nucleotide resolution of DNA methylation in cytosine-phosphate-guanine (CpG) sites and surrounding regions were obtained from peripheral leukocytes. This study focuses on methylation sites in GWAS-informed genes previously associated with sleep and circadian phenotypes. Linear regression assessed the association between sleep midpoint and sleep regularity with site-specific methylation levels, adjusting for sex, age, race/ethnicity, body mass index, and psychotropic medication use. Using the Benjamini & Hochberg method to adjust for a false discovery rate. Adjusted p-values are reported as q-values. Results Sleep midpoint was not associated with a significant change in methylation at any of the measured intragenic sites. Sleep regularity was significantly associated with differential methylation at 238 intragenic sites in 147 genes with an adjusted p<0.05, of which, three sites were within GWAS-informed sleep/circadian-related genes. Higher sleep irregularity was associated with hypermethylation in MAD1L1 (q=2.4x10-2) and with hypomethylation in CALN1 (q=3.8 x 10-4) and ZNF618 (q=3.8 x 10-2). Conclusion Sleep irregularity is associated with altered DNA methylation in genes previously identified in GWAS of sleep/circadian phenotypes. Our data provides evidence for a potential epigenetic link between sleep irregularity and genes involved in neurocognitive functioning (CALN1), internalizing disorders (MAD1L1) and blood pressure (ZNF618). Support (If Any) National Institutes of Health (R01HL136587, R01MH118308, UL1TR000127)

Sleep variability and regularity as contributors to obesity and cardiometabolic health in adolescence

“…Therefore, there are significant inequalities and health disparities in sleep–wake patterns at play that warrant further investigation. Finally, the role of genetics/epigenetics is a critical scientific gap that needs to be addressed, as preliminary studies suggest that sleep irregularity may be associated with altered DNA methylation in genes previously associated with cardiovascular disorders [98]. Despite all these research needs, current evidence suggests that a stable sleep–wake cycle is essential for preventing adverse health outcomes and managing optimal health in adolescence.…”