Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes

Wang, H.; Lane, Jacqueline M.; Jones, Samuel E.; Dashti, Hassan S.; Ollila, Hanna; Wood, Andrew R.; Hees, Vincent T. van; Brumpton, Ben; Winsvold, Bendik S.; Kantojärvi, Katri; Palviainen, Teemu; Cade, Brian E.; Sofer, Tamar; Song, Yanwei; Patel, Krunal; Anderson, S. G.; Bowden, Jack; Emsley, Richard; Kyle, S D; Little, Max A.; Loudon, Andrew; Scheer, Frank A.J.L.; Purcell, Shaun; Richmond, Rebecca C; Spiegelhalder, Kai; Tyrrell, Jessica; Zhu, Xiaofeng; Hublin, Christer; Kaprio, Jaakko; Kristiansson, Kati; Sulkava, Sonja; Paunio, Tiina; Hveem, Kristian; Nielsen, Jonas B.; Willer, Cristen J.; Zwart, JA; Strand, Linn Beate; Frayling, T M; Ray, David; Lawlor, Deborah A; Rutter, Martin K; Weedon, Michael N.; Redline, Susan; Saxena, Richa

doi:10.1016/j.sleep.2019.11.1140

Cited by 26 publications

(52 citation statements)

References 40 publications

(59 reference statements)

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“…Sleep lengths in twins have been similar as in other Finnish studies [ 27 ]. In addition, our twin cohort has taken part in multiple genome-wide association studies, with cohort specific effect size estimates that do not differ from the meta-analysis results [ 35 , 36 ]. The results are also valuable from an ontogeny point of view.…”

Section: Discussionmentioning

confidence: 99%

Changes in self-reported sleep duration with age - a 36-year longitudinal study of Finnish adults

2020

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Background Sleep deprivation is often claimed to be increasingly common, but most studies show small changes in sleep duration over the last decades. Our aim was to analyze long-term patterns in self-reported sleep duration in a population-based cohort. Methods Members of the Older Finnish Twin Cohort have responded to questionnaires in 1975 (N = 30,915 individuals, response rate 89%, mean age 36 years), 1981 (24,535, 84%, 41 years), 1990 (12,450, 77%, 44 years), and 2011 (8334, 72%, 60 years). Weibull regression models were used to model the effects of follow-up time and age simultaneously. Results Sleep duration has decreased in all adult age groups and in both genders. The mean duration was in men 7.57 h in 1975 and 7.39 in 2011, and in women 7.69 and 7.37, respectively. The decrease was about 0.5 min in men and 0.9 in women per year of follow-up. In the age-group 18–34 years, mean sleep length was 7.69 h in 1975 and 7.53 in 1990. Among 35–54-year-old it was 7.57 h in 1975 and 7.34 in 2011, and in the age group of 55+ year olds 7.52 and 7.38, correspondingly. The change was largest in middle-aged group: about 23 min or about 0.6 min per year of follow-up. Conclusions There has been a slight decrease in mean sleep duration during the 36-year follow-up. Although the sleep duration was longer in 1970s and 1980s, the probable main cause for the change in this study population is the effect of aging.

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Section: Discussionmentioning

confidence: 99%

Changes in self-reported sleep duration with age - a 36-year longitudinal study of Finnish adults

2020

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“…In this study, we have included the data (summary statistics) of the largest GWAS published to date. These studies had been approved by local ethics committees and had obtained the required informed consents (detailed in previously published papers) [36][37][38][39][40][41]43,44 . The overall study design is shown in Figure 1.…”

Section: Datasetsmentioning

confidence: 99%

“…Number of genes p-value considered* ADHD 42 NA NA Sleep duration 36 48 2.78x10 -6 Long sleep duration 40 14 2.78x10 -6 Short sleep duration 40 32 2.78x10 -6 Daytime sleepiness 38 38 2.78x10 -6 Snoring 36 33 2.78x10 -6 Insomnia 36 44 2.78x10 -6 Insomnia 37 75 2.78x10 -6 Daytime dozing 36 2 2.78x10 -6 Daytime napping 36 8 2.78x10 -6 *p-value of Bonferroni correction test; NA = not-applicable.…”

Section: Phenotypesmentioning

confidence: 99%

Sleep-related traits and attention-deficit/hyperactivity disorder comorbidity: shared genetic risk factors, molecular mechanisms, and causal effects

Carpena

Bonilla

Matijasevich

et al. 2020

Preprint

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Study Objectives: To evaluate the level of shared genetic components between attention-deficit/hyperactivity disorder (ADHD) and sleep phenotype, common pathways between them and a possible causal relationship between traits. Methods: We used summary statistics of the largest genome-wide association studies available for ADHD and sleep-related phenotypes including insomnia, napping, daytime dozing, snoring, ease getting up, daytime sleepiness, sleep duration and chronotype. We estimated the genomic correlation between ADHD and sleep-related traits using cross-trait LD-score regression and investigated potential common mechanisms using gene-based cross-trait metanalyses and functional enrichment analyses. The causal effect between the sleep related traits and ADHD was estimated with two sample Mendelian randomization (TSMR), using the Inverse Variance Weighted method as the main estimator. Results: Positive genomic correlation between insomnia, daytime napping, daytime dozing, snoring, daytime sleepiness, short and long sleep duration, and ADHD were observed. Insomnia, sleep duration, daytime sleepiness, and snoring shared genes with ADHD, which were involved in neurobiological functions and regulatory signaling pathways. The TSMR approach supported a causal effect of insomnia, daytime napping, and short sleep duration on ADHD, and of ADHD on long sleep duration and chronotype. Conclusion: Our findings suggest that the comorbidity between sleep phenotypes and ADHD may be mediated by common genetic factors with an important role on neuronal signaling pathways. In addition, it may also exist a causal effect of sleep disturbances and short sleep duration on ADHD, reinforcing the role of these sleep phenotypes as predictors or early markers of ADHD.

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“…Are these experimental findings in model systems relevant to humans? Our analysis of several self-reported sleep traits ( N = 450,000) in humans of European ancestry from the U.K. Biobank ( 4 – 8 , 24 ) identified genome-wide significant associations of several sleep traits with common variants in the KSR2 and ERBB4 genomic loci. KSR2 is a scaffolding protein that enables interaction of the EGFR signaling components RAF, MEK, and ERK, and thus is crucial for EGFR signaling ( 46 ).…”

Section: Discussionmentioning

confidence: 94%

“…6, A and C to E, and table S1). In addition, pathway analysis for EDS revealed associations at EGFR signaling pathways enriched in the sleep propensity subtype of daytime sleepiness ( 4 ). Together, these results suggest that the identified genetic variants in the ERBB4 and KSR2 loci associate with measures of increased sleep.…”

Section: Resultsmentioning

confidence: 99%

Evolutionarily conserved regulation of sleep by epidermal growth factor receptor signaling

et al. 2019

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The genetic bases for most human sleep disorders and for variation in human sleep quantity and quality are largely unknown. Using the zebrafish, a diurnal vertebrate, to investigate the genetic regulation of sleep, we found that epidermal growth factor receptor (EGFR) signaling is necessary and sufficient for normal sleep levels and is required for the normal homeostatic response to sleep deprivation. We observed that EGFR signaling promotes sleep via mitogen-activated protein kinase/extracellular signal–regulated kinase and RFamide neuropeptide signaling and that it regulates RFamide neuropeptide expression and neuronal activity. Consistent with these findings, analysis of a large cohort of human genetic data from participants of European ancestry revealed that common variants in genes within the EGFR signaling pathway are associated with variation in human sleep quantity and quality. These results indicate that EGFR signaling and its downstream pathways play a central and ancient role in regulating sleep and provide new therapeutic targets for sleep disorders.

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Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes

Cited by 26 publications

References 40 publications

Changes in self-reported sleep duration with age - a 36-year longitudinal study of Finnish adults

Changes in self-reported sleep duration with age - a 36-year longitudinal study of Finnish adults

Sleep-related traits and attention-deficit/hyperactivity disorder comorbidity: shared genetic risk factors, molecular mechanisms, and causal effects

Evolutionarily conserved regulation of sleep by epidermal growth factor receptor signaling

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