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

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

SLEEP ◽

10.1093/sleep/zsy061.013 ◽

2018 ◽

Vol 41 (suppl_1) ◽

pp. A6-A6

Author(s):

H Wang ◽

J M Lane ◽

H S Dashti ◽

S Jones ◽

B E Cade ◽

...

Keyword(s):

Association Analysis ◽

Excessive Daytime Sleepiness ◽

Daytime Sleepiness ◽

Genome Wide Association ◽

Uk Biobank ◽

Genome Wide Association Analysis ◽

Genome Wide ◽

The Uk

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Associations of sleep and circadian phenotypes with COVID-19 susceptibility and hospitalization: an observational cohort study based on the UK Biobank and a two-sample Mendelian randomization study

SLEEP ◽

10.1093/sleep/zsac003 ◽

2022 ◽

Author(s):

Zheran Liu ◽

Yaxin Luo ◽

Yonglin Su ◽

Zhigong Wei ◽

Ruidan Li ◽

...

Keyword(s):

Cohort Study ◽

Excessive Daytime Sleepiness ◽

Daytime Sleepiness ◽

Mendelian Randomization ◽

Causal Link ◽

Uk Biobank ◽

Inverse Variance ◽

Increased Risk ◽

Weighted Median ◽

The Uk

Abstract Study Objectives Sleep and circadian phenotypes are associated with several diseases. The present study aimed to investigate whether sleep and circadian phenotypes were causally linked with coronavirus disease 2019 (COVID-19)-related outcomes. Methods Habitual sleep duration, insomnia, excessive daytime sleepiness, daytime napping, and chronotype were selected as exposures. Key outcomes included positivity and hospitalization for COVID-19. In the observation cohort study, multivariable risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated. Two-sample Mendelian randomization (MR) analyses were conducted to estimate the causal effects of the significant findings in the observation analyses. Beta values and the corresponding 95% CIs were calculated and compared using the inverse variance weighting, weighted median, and MR-Egger methods. Results In the UK Biobank cohort study, both often excessive daytime sleepiness and sometimes daytime napping were associated with hospitalized COVID-19 (excessive daytime sleepiness [often vs. never]: RR=1.24, 95% CI=1.02-1.5; daytime napping [sometimes vs. never]: RR=1.12, 95% CI=1.02-1.22). In addition, sometimes daytime napping was also associated with an increased risk of COVID-19 susceptibility (sometimes vs. never: RR= 1.04, 95% CI=1.01-1.28). In the MR analyses, excessive daytime sleepiness was found to increase the risk of hospitalized COVID-19 (MR IVW method: OR = 4.53, 95% CI = 1.04-19.82), whereas little evidence supported a causal link between daytime napping and COVID-19 outcomes. Conclusions Observational and genetic evidence supports a potential causal link between excessive daytime sleepiness and an increased risk of COVID-19 hospitalization, suggesting that interventions targeting excessive daytime sleepiness symptoms might decrease severe COVID-19 rate.

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

SLEEP ◽

10.1093/sleep/zsz101 ◽

2019 ◽

Vol 42 (8) ◽

Cited By ~ 4

Author(s):

Richard Barfield ◽

Heming Wang ◽

Yongmei Liu ◽

Jennifer A Brody ◽

Brenton Swenson ◽

...

Keyword(s):

Daytime Sleepiness ◽

Cardiovascular Health ◽

Association Studies ◽

Meta Analysis ◽

Health Study ◽

Cardiovascular Health Study ◽

P Value ◽

Uk Biobank ◽

Ethnic Study ◽

The Uk

AbstractStudy ObjectivesDaytime 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).MethodsWe 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.ResultsIn 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.ConclusionsWe 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.

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Sleep and epilepsy—chicken or egg?

10.1093/oso/9780198778240.003.0011 ◽

2018 ◽

Author(s):

Dora A. Lozsadi

Keyword(s):

Side Effects ◽

Sleep Disorders ◽

Learning Disability ◽

Excessive Daytime Sleepiness ◽

Daytime Sleepiness ◽

Seizure Control ◽

Subjective Sleep ◽

Neurological Conditions ◽

The Uk ◽

Patients With Epilepsy

Epilepsy is the commonest serious chronic neurological condition, affecting 0.5% of the population in the UK. Subjective sleep disturbance and excessive daytime sleepiness are reported to be 50% more frequent in those with epilepsy than in controls. Causes are multiple. Both poor seizure control and nocturnal attacks are known to contribute to such sleep disorders. Epilepsy also increases the risk of associated sleep disorders, and additional neurological conditions, such as dementia, learning disability, and depression. These all affect sleep hygiene. Prescribed anti-epileptic drugs will further aggravate the problem. Side-effects will include drowsiness. Sedating benzodiazepines and barbiturates are considered worst offenders. Others affect sleep architecture to varying degrees and/or cause insomnia. While hyper-somnolence in patients with epilepsy will raise the possibility of any of the above issues, sleep deprivation is one of the commonest seizure triggers. This chapter will shed more light on the intricate relationship between sleep and epilepsy.

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The effect of socioeconomic deprivation on the association between an extended measurement of unhealthy lifestyle factors and health outcomes: a prospective analysis of the UK Biobank cohort

The Lancet Public Health ◽

10.1016/s2468-2667(18)30200-7 ◽

2018 ◽

Vol 3 (12) ◽

pp. e576-e585 ◽

Cited By ~ 35

Author(s):

Hamish M E Foster ◽

Carlos A Celis-Morales ◽

Barbara I Nicholl ◽

Fanny Petermann-Rocha ◽

Jill P Pell ◽

...

Keyword(s):

Health Outcomes ◽

Lifestyle Factors ◽

Socioeconomic Deprivation ◽

Prospective Analysis ◽

Uk Biobank ◽

Unhealthy Lifestyle ◽

The Uk

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The integration of genetically-regulated transcriptomics and electronic health records highlights a pattern of medical outcomes related to increased hepatic Transthyretin expression

10.1101/2021.07.14.21260525 ◽

2021 ◽

Author(s):

Gita A Pathak ◽

Antonella De Lillo ◽

Frank Wendt ◽

Flavio De Angelis ◽

Dora Koller ◽

...

Keyword(s):

Electronic Health Records ◽

Health Outcomes ◽

Bone Fracture ◽

Neuronal Response ◽

Genetic Regulation ◽

Uk Biobank ◽

Health Records ◽

Hepatic Expression ◽

Electronic Health ◽

The Uk

Background: Transthyretin (TTR) is a multi-function protein involved in the systemic transport of retinol and thyroxine. It also participates in the neuronal response to stress and proteolysis of few specific substrates. TTR is also the precursor of the fibrils that compromise organ function in the familial and sporadic systemic amyloidoses (ATTR). RNA-interference and anti-sense therapeutics targeting TTR hepatic transcription have been shown to reduce TTR amyloid formation. The goal of our study was to investigate the role of genetic regulation of TTR transcriptomic variation in human traits and diseases. Methods and Findings: We leveraged genetic and phenotypic information from the UK Biobank and transcriptomic profiles from the GTEx (Genotype-Tissue Expression) project to test the association of genetically regulated TTR gene expression with 7,149 traits assessed in 420,531 individuals. We conducted a joint multi-tissue analysis of TTR transcription regulation and identified an association with a specific operational procedure related to secondary open reduction of fracture of bone (p=5.46x10-6, false discovery rate q=0.039). Using tissue-specific TTR cis expression quantitative trait loci, we demonstrated that the association is driven by the genetic regulation of TTR hepatic expression (odds ratio [OR] = 3.46, 95% confidence interval [CI] = 1.85-6.44, p = 9.51x10-5). Although there is an established relationship of retinol and thyroxine abnormalities with bone loss and the risk of bone fracture, this is the first evidence of a possible effect of TTR transcriptomic regulation. Investigating the UK Biobank electronic health records available, we investigated the comorbidities affecting individuals undergoing the specific surgical procedure. Excluding medical codes related to bone fracture events, we identified a pattern of health outcomes that have been previously associated with ATTR manifestations. These included osteoarthritis (OR=3.18, 95%CI=1.93-4.25, p=9.18x10-8), carpal tunnel syndrome (OR=2.15, 95%CI=1.33-3.48, p=0.002), and a history of gastrointestinal diseases (OR=2.01, 95%CI=1.33-3.01, p=8.07x10-4). Conclusions: The present study supports the notion that TTR hepatic expression can affect health outcomes linked to physiological and pathological processes presumably related to the encoded protein. Our findings highlight how the integration of omics information and electronic health records can successfully dissect the complexity of multi-function proteins such as TTR.

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