0014 Genome-wide Association Analysis Of Excessive Daytime Sleepiness In The Uk Biobank Identifies 42 Novel Loci

AbstractStudy ObjectivesExcessive 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).MethodsWe 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.Results61 methylation sites were associated with ESS (FDR ≤ 0.1) in African Americans only, including an association inKCTD5, 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 geneRAI1, a gene associated with sleep and circadian phenotypes. In a follow-up analysis, a genetic variant withinRAI1associated with both DNAm and sleepiness score. The variant’s association with sleepiness was replicated in the UK Biobank.ConclusionsOur 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 SignificanceExcessive 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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Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits

10.1101/082792 ◽

2016 ◽

Cited By ~ 1

Author(s):

Jacqueline M. Lane ◽

Jingjing Liang ◽

Irma Vlasac ◽

Simon G. Anderson ◽

David A. Bechtold ◽

...

Keyword(s):

Sleep Duration ◽

Excessive Daytime Sleepiness ◽

Daytime Sleepiness ◽

Sleep Disturbances ◽

Metabolic Diseases ◽

Genome Wide Association ◽

Association Analyses ◽

Genome Wide ◽

The Uk ◽

Insomnia Symptoms

Chronic sleep disturbances, associated with cardio-metabolic diseases, psychiatric disorders and all-cause mortality1,2, affect 25–30% of adults worldwide3. While environmental factors contribute importantly to self-reported habitual sleep duration and disruption, these traits are heritable4–9, and gene identification should improve our understanding of sleep function, mechanisms linking sleep to disease, and development of novel therapies. We report single and multi-trait genome-wide association analyses (GWAS) of self-reported sleep duration, insomnia symptoms including difficulty initiating and/or maintaining sleep, and excessive daytime sleepiness in the UK Biobank (n=112,586), with discovery of loci for insomnia symptoms (near MEIS1, TMEM132E, CYCL1, TGFBI in females and WDR27 in males), excessive daytime sleepiness (near AR/OPHN1) and a composite sleep trait (near INADL and HCRTR2), as well as replication of a locus for sleep duration (at PAX-8). Genetic correlation was observed between longer sleep duration and schizophrenia (rG=0.29, p=1.90x10−13) and between increased excessive daytime sleepiness and increased adiposity traits (BMI rG=0.20, p=3.12x10−09; waist circumference rG=0.20, p=2.12x10−07).

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