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Sleep. 2019 May 29. pii: zsz101. doi: 10.1093/sleep/zsz101. [Epub ahead of print]

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

Barfield R1,2, Wang H3,4,5, Liu Y6, Brody JA7, Swenson B7,8, Li R4,9, Bartz TM7,8, Sotoodehnia N7, Chen YI10, Cade BE3,4,5, Chen H9,11,12, Patel SR13, Zhu X14, Gharib SA15, Johnson WC16, Rotter JI10, Saxena R3,4,5,17, Purcell S3,18, Lin X9,19, Redline S4,5,20, Sofer T4,5,9.

Author information

1
Department of Epidemiology, University of Washington, Seattle, WA.
2
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
3
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
4
Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA.
5
Division of Sleep Medicine, Harvard Medical School, Boston, MA.
6
Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC.
7
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
8
Institute for Public Health Genetics, University of Washington, Seattle, WA.
9
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA.
10
The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.
11
Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
12
Center for Precision Health, School of Public Health & School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX.
13
Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA.
14
Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH.
15
Computational Medicine Core, Center for Lung Biology, University of Washington Medicine Sleep Center, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle, WA.
16
Department of Biostatistics, University of Washington, Seattle, WA.
17
Center for Genomic Medicine and Department of Anesthesia, Pain, and Critical Care Medicine, Massachusetts General Hospital, Boston, MA.
18
Department of Psychiatry, Brigham & Women's Hospital, Harvard Medical School, Boston, MA.
19
Department of Statistics, Harvard University, Cambridge, MA.
20
Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA.

Abstract

STUDY OBJECTIVES:

Daytime sleepiness is a consequence of inadequate sleep, sleep-wake control disorder, or other medical conditions. Population variability in prevalence of daytime sleepiness is likely due to genetic and biological factors as well as social and environmental influences. DNA methylation (DNAm) potentially influences multiple 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 the Multi-Ethnic Study of Atherosclerosis (MESA; n = 619) and the Cardiovascular Health Study (n = 483), with cross-study replication and meta-analysis. Genetic variants near ESS-associated DNAm were analyzed for methylation quantitative trait loci and followed with replication of genotype-sleepiness associations in the UK Biobank.

RESULTS:

In MESA only, we detected four DNAm-ESS associations: one across all race/ethnic groups; three in African-Americans (AA) only. Two of the MESA AA associations, in genes KCTD5 and RXRA, nominally replicated in CHS (p-value < 0.05). In the AA meta-analysis, we detected 14 DNAm-ESS associations (FDR q-value < 0.05, top association p-value = 4.26 × 10-8). Three DNAm sites mapped to genes (CPLX3, GFAP, and C7orf50) with biological relevance. We also found evidence for associations with DNAm sites in RAI1, a gene associated with sleep and circadian phenotypes. UK Biobank follow-up analyses detected SNPs in RAI1, RXRA, and CPLX3 with nominal sleepiness associations.

CONCLUSIONS:

We identified methylation sites in multiple genes possibly implicated in daytime sleepiness. Most significant DNAm-ESS associations were specific to AA. Future work is needed to identify mechanisms driving ancestry-specific methylation effects.

KEYWORDS:

diversity; epigenetics; excessive daytime sleepiness; genomics; methylation; race/ethnic heterogeneity; sleep–wake

PMID:
31139831
DOI:
10.1093/sleep/zsz101

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