Epigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American specific associations

Abstract

3 Study Objectives: Excessive daytime sleepiness (EDS) is a consequence of inadequate sleep, or of a primary disorder of sleep-wake control. Population variability in prevalence of EDS and susceptibility to EDS are likely due to genetic and biological factors as well as social and environmental influences. Epigenetic modifications (such as DNA methylation-DNAm) are potential influences on a range of health outcomes. Here, we explored the association between DNAm and daytime sleepiness quantified by the Epworth Sleepiness Scale (ESS). Methods:We performed multi-ethnic and ethnic-specific epigenome-wide association studies for DNAm and ESS in 619 individuals from the Multi-Ethnic Study of Atherosclerosis. Replication was assessed in the Cardiovascular Health Study (CHS). Genetic variants in genes proximal to ESS-associated DNAm were analyzed to identify methylation quantitative trait loci and followed with replication of genotype-sleepiness associations in the UK Biobank.Results: 61 methylation sites were associated with ESS (FDR ≤ 0.1) in African Americans only, including an association in KCTD5, a gene strongly implicated in sleep. One association (cg26130090) replicated in CHS African Americans (p-value 0.0004). We identified a sleepinessassociated methylation site in the gene RAI1, a gene associated with sleep and circadian phenotypes. In a follow-up analysis, a genetic variant within RAI1 associated with both DNAm and sleepiness score. The variant's association with sleepiness was replicated in the UK Biobank. Conclusions:Our analysis identified methylation sites in multiple genes that may be implicated in EDS. These sleepiness-methylation associations were specific to African Americans. Future work is needed to identify mechanisms driving ancestry-specific methylation effects. 4Excessive daytime sleepiness is associated with negative health outcomes such as reduction in quality of life, increased workplace accidents, and cardiovascular mortality. There are race/ethnic disparities in excessive daytime sleepiness, however, the environmental and biological mechanisms for these differences are not yet understood. We performed an association analysis of DNA methylation, measured in monocytes, and daytime sleepiness within a racially diverse study population. We detected numerous DNA methylation markers associated with daytime sleepiness in African Americans, but not in European and Hispanic Americans. Future work is required to elucidate the pathways between DNA methylation, sleepiness, and related behavioral/environmental exposures. analysis using the lumi Bioconductor package 37 . These included color bias adjustments via smooth quantile normalization, median background adjustment, standard quantile adjustment, checks for potential sex or race mismatches, and outlier detection via multidimensional plots.Additional details on pre-processing of the DNAm data can be found in Liu et al 34 . Following DNAm preprocessing, each of 484,882 methylation probes for each person has a Beta-value, representing the proportion ...

Associations Between Sleep Quality and Health Span: A Prospective Cohort Study Based on 328,850 UK Biobank Participants

“…We also observed a decreased risk of terminated health span for single low-risk sleep behaviors, such as “sleep duration 7–8 h/day,” “no daytime sleepiness,” “never/rarely insomnia/sleeplessness,” and “early chronotype.” Similarly, high-risk sleep behavioral factors including “late chronotype” ( Merikanto et al, 2013 ; Erren et al, 2016 ), “abnormal sleep duration” ( Mesas et al, 2010 ; Cappuccio et al, 2011 ; Rudnicka et al, 2017 ; Daghlas et al, 2019 ), “frequently experience insomnia/sleeplessness” ( Hsu et al, 2015 ; Javaheri and Redline, 2017 ), “habitual snoring” ( Seidel et al, 2012 ; Sands et al, 2013 ; Li et al, 2015 ), and “excessive daytime sleepiness” ( Blachier et al, 2012 ; Boden-Albala et al, 2012 ; Barfield et al, 2019 ) were associated with increased risk of chronic disease morbidity and mortality. If all these five high-risk sleep behaviors were rectified appropriately, nearly 15% of terminated health span would have been prevented, highlighting the importance of adhering to healthy sleep behaviors.…”

Epigenetics of Sleep Disruption

“…Future studies must consider racial and ethnic disparities while designing epigenetic studies regarding sleep and sleep disruptions. An association analysis study consisting of a racially diverse population [147] measured DNA methylation in monocytes to identify whether a link exists between these markers and daytime sleepiness, and it was found that most significant DNA methylation was specific to African Americans [147].…”