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

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Abstract 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 sleepiness-associated 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. Statement of Significance Excessive 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.

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