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Liver Kinase B1 (LKB1) is known as a master kinase for 14 kinases related to the adenosine monophosphate-activated protein kinase. Two of them salt inducible kinase 3 and adenosine monophosphate-activated protein kinase α have previously been implicated in sleep regulation. We generated loss-of-function mutants for Lkb1 in both Drosophila and mice. Sleep, but not circadian rhythms, was reduced in Lkb1-mutant flies and in flies with neuronal deletion of Lkb1. Genetic interactions between Lkb1 and threonine to alanine mutation at residue 184 of adenosine monophosphate-activated protein kinase in Drosophila sleep or those between Lkb1 and Threonine to Glutamic Acid mutation at residue 196 of salt inducible kinase 3 in Drosophila viability have been observed. Sleep was reduced in mice after virally mediated reduction of Lkb1 in the brain. Electroencephalography analysis showed that nonrapid eye movement sleep and sleep need were both reduced in Lkb1-mutant mice. These results indicate that liver kinase B1 plays a physiological role in sleep regulation conserved from flies to mice., (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Sleep problems and substance use frequently co-occur. While substance use can result in specific sleep deficits, genetic pleiotropy could explain part of the relationship between sleep and substance use and use disorders. Here we use the largest publicly available genome-wide summary statistics of substance use behaviours (N = 79,729-632,802) and sleep/activity phenotypes to date (N = 85,502-449,734) to (1) assess the genetic overlap between substance use behaviours and both sleep and circadian-related activity measures, (2) estimate clusters from genetic correlations and (3) test processes of causality versus genetic pleiotropy. We found 31 genetic correlations between substance use and sleep/activity after Bonferroni correction. These patterns of overlap were represented by two genetic clusters: (1) tobacco use severity (age of first regular tobacco use and smoking cessation) and sleep health (sleep duration, sleep efficiency and chronotype) and (2) substance consumption/problematic use (drinks per day and cigarettes per day, cannabis use disorder, opioid use disorder and problematic alcohol use) and sleep problems (insomnia, self-reported short sleep duration, increased number of sleep episodes, increased sleep duration variability and diurnal inactivity) and measures of circadian-related activity (L5, M10 and sleep midpoint). Latent causal variable analyses determined that horizontal pleiotropy (rather than genetic causality) underlies a majority of the associations between substance use and sleep/circadian related measures, except one plausible genetically causal relationship for opioid use disorder on self-reported long sleep duration. Results show that shared genetics are likely a mechanism that is at least partly responsible for the overlap between sleep and substance use traits., (© 2022 Society for the Study of Addiction.)

Currently, the causal association between sleep disorders and rheumatoid arthritis (RA) has been poorly understood. In this two-sample Mendelian randomization (TSMR) study, we tried to explore whether sleep disorders are causally associated with RA. Seven sleep-related traits were chosen from the published Genome-Wide Association Study (GWAS): short sleep duration, frequent insomnia, any insomnia, sleep duration, getting up, morningness (early-to-bed/up habit), and snoring, 27, 53, 57, 57, 70, 274, and 42 individual single-nucleotide polymorphisms (SNPs) ( P < 5 × 10 -8 ) were obtained as instrumental variables (IVs) for these sleep-related traits. Outcome variables were obtained from a public GWAS study that included 14,361 cases and 43,923 European Ancestry controls. The causal relationship between sleep disturbances and RA risk were evaluated by a two-sample Mendelian randomization (MR) analysis using inverse variance weighted (IVW), MR-Egger regression, weighted median, and weight mode methods. MR-Egger Regression and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) were used to test for horizontal pleomorphism and outliers. There was no evidence of a link between RA and frequent insomnia (IVW, odds ratio (OR): 0.99; 95% interval (CI): 0.84-1.16; P = 0.858), any insomnia (IVW, OR: 1.09; 95% CI: 0.85-1.42; P = 0.489), sleep duration (IVW, OR: 0.65, 95% CI: 0.38-1.10, P = 0.269), getting up (IVW, OR: 0.56, 95% CI: 0.13-2.46, P = 0.442), morningness (IVW, OR: 2.59; 95% CI: 0.73-9.16; P = 0.142), or snoring (IVW, OR: 0.95; 95% CI: 0.68-1.33; P = 0.757). Short sleep duration (6h) had a causal effect on RA, as supported by IVW and weighted median (OR: 1.47, 95% CI: 1.12-1.94, P = 0.006; OR: 1.43, 95%CI:1.01-2.05, P = 0.047). Sensitivity analysis showed that the results were stable. Our findings imply that short sleep duration is causally linked to an increased risk of RA. Therefore, sleep length should be considered in disease models, and physicians should advise people to avoid short sleep duration practices to lower the risk of RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gao, Sang, Jia, Zhang, Li, Wei and Wu.)

Objective: To explore the relationship between sleep habits (sleep duration, sleep efficiency, sleep onset timing) and ischemic stroke, and whether there is an interaction between sleep habits and ischemic stroke susceptibility gene loci., Methods: A questionnaire survey, physical examination, blood biochemical testing and genotyping were conducted among rural residents in Beijing, and the gene loci of ischemic stroke suggested by previous genome-wide association studies (GWAS) were screened. Multivariable generalized linear model was used to analyze the correlation between sleep habits, sleep-gene interaction and ischemic stroke., Results: A total of 4 648 subjects with an average age of (58.5±8.7) years were enrolled, including 1 316 patients with ischemic stroke. Compared with non-stroke patients, stroke patients with sleep duration ≥9 hours, sleep efficiency < 80%, and sleep onset timing earlier than 22:00 accounted for a higher proportion ( P < 0.05). There was no significant association between sleep duration and risk of ischemic stroke ( OR =1.04, 95% CI : 0.99-1.10, P =0.085). Sleep efficiency was inversely associated with the risk of ischemic stroke ( OR =0.18, 95% CI : 0.06-0.53, P =0.002). The risk of ischemic stroke in the subjects with sleep efficiency < 80% was 1.47-fold (95% CI : 1.03-2.10, P =0.033) of that in the subjects with sleep efficiency ≥80%. Falling asleep earlier than 22:00 was associated with 1.26 times greater risk of stroke than falling asleep between 22:00 and 22:59 (95% CI : 1.04-1.52, P =0.017). Multifactorial adjustment model showed that rs579459 on ABO gene had an interaction with sleep time ( P for interaction =0.040). When there were two T alleles for rs579459 on the ABO gene, those who fell asleep before 22:00 had 1.56 times (95% CI : 1.20-2.04, P =0.001) the risk of stroke compared with those who fell asleep between 22:00 and 22:59, and there was no significant difference when the number of pathogenic alleles was 0 or 1. In the model adjusted only for gender, age and family structure, sleep duration and the number of T allele rs2634074 on PITX2 gene had an interaction with ischemic stroke ( P for interaction=0.033)., Conclusion: Decreased sleep efficiency is associated with increased risk of ischemic stroke, and falling asleep earlier than 22:00 is associated with higher risk of ischemic stroke. Sleep onset timing interacted with rs579459 in ABO gene and the risk of ischemic stroke. Sleep duration and PITX2 rs2634074 may have a potential interaction with ischemic stroke risk.

A correlation between sleep and systemic lupus erythematosus (SLE) has been observed in a number of prior investigations. However, little is known regarding the potential causative relationship between them. In this study, we selected genetic instruments for sleep traits from pooled data from published genome-wide association studies (GWAS). Independent genetic variants associated with six sleep-related traits (chronotype, sleep duration, short sleep duration, long sleep duration, insomnia, and daytime sleepiness) were selected as instrumental variables. A two-sample Mendelian randomization (TSMR) study was first conducted to assess the causal relationship between sleep traits and SLE (7219 cases versus 15,991 controls). The reverse MR analysis was then used to infer the causal relationship between SLE and sleep traits. Inverse variance weighted (IVW), MR Egger, Weighted median, and Weighted mode were applied to perform the primary MR analysis. MR Egger regression and the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test were used to detect horizontal pleiotropy, and Cochran's Q was used to detect heterogeneity. In studies of the effect of sleep traits on SLE risk, the IVW method demonstrated no causal relationship between chronotype, sleep duration, short sleep duration, long sleep duration, insomnia, daytime sleepiness and SLE risk. The remaining three methods agreed with the results of IVW. In studies of the effect of SLE on the risk of sleep traits, neither IVW, MR Egger, Weighted median, nor Weighted mode methods provided evidence of a causal relationship between SLE and the risk of sleep traits. Overall, our study found no evidence of a bidirectional causal relationship between genetically predicted sleep traits and SLE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sang, Gao, Zhang, Wu, Wu and Wu.)

Background: Observational studies suggest that sleep disturbances are commonly associated with schizophrenia. However, it is uncertain whether this relationship is causal. To investigate the bidirectional causal relation between sleep traits and schizophrenia, we performed a two-sample bidirectional Mendelian randomization (MR) study with the fixed effects inverse-variance weighted (IVW) method., Methods: As genetic variants for sleep traits, we selected variants from each meta-analysis of genome-wide association studies (GWASs) conducted using data from the UK Biobank (UKB)., Results: We found that morning diurnal preference was associated with a lower risk of schizophrenia, while long sleep duration and daytime napping were associated with a higher risk of schizophrenia. Multivariable MR analysis also showed that sleep duration was associated with a higher risk of schizophrenia after adjusting for other sleep traits. Furthermore, genetically predicted schizophrenia was negatively associated with morning diurnal preference and short sleep duration and was positively associated with daytime napping and long sleep duration., Conclusions: Therefore, sleep traits were identified as a potential treatment target for patients with schizophrenia., (© 2022. The Author(s).)

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. Odds ratios (ORs) 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., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Work stress has been found to be associated with sleep quality in various occupational groups, and genetic factors such as variable number tandem repeat polymorphism in the Period3 (Per3) gene also influence the circadian sleep-wake process. Therefore, the present study aimed to evaluate the sleep quality status of non-manual workers in Xinjiang, China and to analyse the effects of work stress and Per3 gene polymorphism and their interaction on sleep quality. A cluster sampling method was used to randomly select 1700 non-manual workers in Urumqi, Xinjiang. The work stress and sleep quality of these workers were evaluated using the Effort−Reward Imbalance Inventory (ERI) and the Pittsburgh Sleep Quality Index (PSQI). Next, 20% of the questionnaire respondents were randomly selected for genetic polymorphism analysis. The polymerase chain reaction-restriction fragment length polymorphism technique was used to determine Per3 gene polymorphism. The detection rate of sleep quality problems differed between the different work stress groups (p < 0.05), suggesting that non-manual workers with high levels of work stress are more likely to have sleep quality problems. Regression analysis revealed that the Per3 gene (OR = 3.315, 95% CI: 1.672−6.574) was the influencing factor for poor sleep quality after adjusting for confounding factors, such as occupation, length of service, education, and monthly income. Interaction analysis showed that Per34/5,5/5 × high work stress (OR = 2.511, 95% CI: 1.635−3.855) had a higher risk of developing sleep quality problems as compared to Per34/4 × low work stress after adjusting for confounding factors. The structural equation modelling showed no mediating effect between work stress and Per3 gene polymorphism. The results of this study show that both work stress and Per3 gene polymorphism independently affect sleep quality of nonmanual workers from Xinjiang, and the interaction between these two factors may increase the risk of sleep quality problems. Therefore, to improve sleep quality, individuals with genetic susceptibility should avoid or reduce as much as possible self-stimulation by work-related exposures such as high levels of external work stress.

Background: Circadian Locomotor Output Cycles Kaput (CLOCK), an essential element of the positive regulatory arm in the human biological clock, is involved in metabolic regulation. The aim was to investigate the behavioral (sleep duration, food timing, dietary intake, appetite and chronobiologic characteristics) and hormonal (plasma ghrelin and Glucagon-like peptide-1 concentrations) factors that could explain the previously reported association between the CLOCK 3111 T/C SNP and obesity., Methods: This cross-sectional study included 403 subjects, overweight and/or obesity, aged 20- 50 years from Iran. The CLOCK rs1801260 data were measured by the PCR-RFLP method. Dietary intake, food timing, sleep duration, appetite and Chrono-type were assessed using validated questionnaires. Ghrelin and GLP-1 were measured by ELIZA in plasma samples. Participants were also divided into three groups based on BMI. Logistic regression models and general linear regression models were used to assess the association between CLOCK genotype and study parameters. Univariate linear regression models were used to assess the interaction between CLOCK and VAS, Food timing, chronotype and sleep on food intakes., Results: After controlling for confounding factors, there was a significant difference between genotypes for physical activity (P = 0.001), waist circumference (P˂0.05), BMI (˂0.01), weight (P = 0.001), GLP-1 (P = 0.02), ghrelin (P = 0.04), appetite (P˂0.001), chronotype (P˂0.001), sleep (P˂0.001), food timing (P˂0.001), energy (P˂0.05), carbohydrate (P˂0.05) and fat intake (P˂0.001). Our findings also show that people with the minor allele C who ate lunch after 3 PM and breakfast after 9 AM are more prone to obesity (P˂0.05). furthermore, there was significant interactions between C allele carrier group and high appetite on fat intake (Pinteraction = 0.041), eat lunch after 3 PM on energy intake (Pinteraction = 0.039) and morning type on fat intake (Pinteraction = 0.021)., Conclusion: Sleep reduction, changes in ghrelin and GLP-1 levels, changes in eating behaviors and evening preference that characterized CLOCK 3111C can all contribute to obesity. Furthermore, the data demonstrate a clear relationship between the timing of food intake and obesity. Our results support the hypothesis that the influence of the CLOCK gene may extend to a wide range of variables related to human behaviors., (© 2022. The Author(s).)

The aim of the present study was to develop a Polygenic Score-based model for molecular chronotype assessment. Questionnaire-based phenotypical chronotype assessment was used as a reference. In total, 54 extremely morning/morning (MM/M; 35 females, 39.7 ± 3.8 years) and 44 extremely evening/evening (EE/E; 20 females, 27.3 ± 7.7 years) individuals donated a buccal DNA sample for genotyping by sequencing of the entire genetic variability of 19 target genes known to be involved in circadian rhythmicity and/or sleep duration. Targeted genotyping was performed using the single primer enrichment technology and a specifically designed panel of 5526 primers. Among 2868 high-quality polymorphisms, a cross-validation approach lead to the identification of 83 chronotype predictive variants, including previously known and also novel chronotype-associated polymorphisms. A large (35 single-nucleotide polymorphisms [SNPs]) and also a small (13 SNPs) panel were obtained, both with an estimated predictive validity of approximately 80%. Potential mechanistic hypotheses for the role of some of the newly identified variants in modulating chronotype are formulated. Once validated in independent populations encompassing the whole range of chronotypes, the identified panels might become useful within the setting of both circadian public health initiatives and precision medicine.

Sleep is an essential state that allows for recuperation and survival processes. Disturbing sleep triggers stress responses that promote protective gene expression. Sleep and its deprivation grossly impact gene expression, but little is known about how normal or disturbed sleep control gene expression. Central to the induction of sleep are sleep-active neurons, which inhibit wakefulness and promote survival. Sleep and sleep-active neurons are highly conserved. In Caenorhabditis elegans, the sleep-active RIS neuron is crucial for sleep and survival. Here, we show that RIS depolarization promotes the protective gene expression response that occurs during developmental arrest. This response includes the activation of FOXO/DAF-16 and expression of DAF-16 target genes such as HSP-12.6, a small heat-shock protein that is required for starvation survival. Disturbing sleep by mechanical stimulation increases RIS depolarization. RIS activation in turn activates DAF-16 and other genes required for survival. Hence, during normal sleep, RIS depolarization promotes protective gene expression. When sleep is disturbed, protective gene expression gets further increased by raised RIS depolarization. We thus link sleep-active neuron depolarization to protective gene expression changes and suggest that the cellular stress response following sleep deprivation could be understood as a safeguarding process that is caused by the overactivation of sleep-active neurons., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Childhood overweight/obesity is a global public health concern. It is important to identify its early-life risk factors. Maternal poor sleep is common in late pregnancy, and previous studies indicated that poor sleep may influence the offspring's adiposity status. However, very few studies in humans investigated the effect of the different sleep parameters (sleep quantity, quality, and timing) on the offspring's adiposity indicators, and long-term studies are even more scarce. In addition, the underlying mechanism remains unclear. The present study therefore aimed to examine the association between the three maternal sleep dimensions in the late pregnancy and the offspring adiposity indicators and to explore the potential mediating effect of the cord blood DNA methylation in the above association., Methods: Included participants in the current study were 2211 healthy pregnant women with singleton gestation from the Shanghai Birth Cohort (SBC) and Shanghai Sleep Birth Cohort (SSBC). Maternal nighttime sleep duration, quality, and midpoint (an indicator of circadian rhythm) were assessed by the same instrument in both cohorts during late pregnancy, and the offspring's body mass index (BMI) and subcutaneous fat (SF) were measured at 2 years old. Additionally, in 231 SSBC samples, the genome-wide DNA methylation levels were measured using the Illumina Infinium Methylation EPIC BeadChip. The multivariate linear regression was used to determine the associations between the maternal sleep parameters and the offspring adiposity indicators. The epigenome-wide association study was conducted to identify the maternal sleep-related CpG sites. The mediation analysis was performed to evaluate the potential intermediate role of DNA methylation in the association between maternal sleep and offspring adiposity indicators., Results: The mean maternal nighttime sleep duration and the sleep midpoint for combined cohorts were 9.24 ± 1.13 h and 3.02 ± 0.82, respectively, and 24.5% of pregnant women experienced poor sleep quality in late pregnancy. After adjusting for the covariates, the maternal later sleep midpoint was associated with the increased SF in offspring (Coef. = 0.62, 95% CI 0.37-0.87, p < 0.001) at 2 years old. However, no significant associations of the nighttime sleep duration or sleep quality with the offspring adiposity indicators were found. In the SSBC sample, 45 differential methylated probes (DMPs) were associated with the maternal sleep midpoint, and then, we observed 10 and 3 DMPs that were also associated with the offspring's SF and BMI at 2 years, of which cg04351668 (MARCH9) and cg12232388 significantly mediated the relationship of sleep midpoint and SF and cg12232388 and cg12225226 mediated the sleep midpoint-BMI association, respectively., Conclusions: Maternal later sleep timing in late pregnancy was associated with higher childhood adiposity in the offspring. Cord blood DNA methylation may play a mediation role in that relationship., (© 2022. The Author(s).)

Background and Purpose: Sleep characteristics, including taking a nap and sleep apnea, have been proven to have effects on cognitive function, and apolipoprotein E polymorphism ε4 (APOEε4) has been confirmed to be a risk factor for mild cognitive impairment (MCI), but epidemiological studies linking sleep characteristics and APOEε4 are scarce. We aimed to explore the longitudinal association between sleep characteristics and MCI in an overall cohort, in APOEε4 carriers and in APOEε4 non-carriers., Methods: We included 3053 older adults from the Tianjin Elderly Nutrition and Cognition Cohort (TENCC) study, recruited from March 2018 to June 2019, and followed up from March 2021 to June 2021. All participants underwent detailed neuropsychological evaluation that allowed psychometric MCI classification. Information on self-reported sleep characteristics was gathered via face-to-face interviews. Crude and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression models., Results: In the multivariable-adjusted models, taking a nap at noon was associated with decreased risk of MCI in all participants (yes vs. no: HR 0.723, 95% CI 0.592, 0.883) and in APOEε4 non-carriers (yes vs. no: HR 0.719, 95% CI 0.576, 0.897). Sleep apnea was associated with increased risk of MCI in all participants (vs. good: HR 2.213, 95% CI 1.171, 4.180) and in APOEε4 non-carriers (vs. good: HR 2.217, 95% CI 1.085, 4.529)., Conclusions: This study suggests that taking a nap at noon might be a potential protective factor against development of MCI in APOEε4 non-carriers, and sleep apnea might be associated with increased incidence of MCI in APOEε4 non-carriers., (© 2022 European Academy of Neurology.)

Sleep duration, psychiatric disorders and dementias are closely interconnected in older adults. However, the underlying genetic mechanisms and brain structural changes are unknown. Using data from the UK Biobank for participants primarily of European ancestry aged 38-73 years, including 94% white people, we identified a nonlinear association between sleep, with approximately 7 h as the optimal sleep duration, and genetic and cognitive factors, brain structure, and mental health as key measures. The brain regions most significantly underlying this interconnection included the precentral cortex, the lateral orbitofrontal cortex and the hippocampus. Longitudinal analysis revealed that both insufficient and excessive sleep duration were significantly associated with a decline in cognition on follow up. Furthermore, mediation analysis and structural equation modeling identified a unified model incorporating polygenic risk score (PRS), sleep, brain structure, cognition and mental health. This indicates that possible genetic mechanisms and brain structural changes may underlie the nonlinear relationship between sleep duration and cognition and mental health., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Hypocretin (Hcrt), also known as orexin, neuropeptide signaling stabilizes sleep and wakefulness in all vertebrates. A lack of Hcrt causes the sleep disorder narcolepsy, and increased Hcrt signaling has been speculated to cause insomnia, but while the signaling pathways of Hcrt are relatively well-described, the intracellular mechanisms that regulate its expression remain unclear. Here, we tested the role of microRNAs (miRNAs) in regulating Hcrt expression. We found that miR-137, miR-637, and miR-654-5p target the human HCRT gene. miR-137 is evolutionarily conserved and also targets mouse Hcrt as does miR-665. Inhibition of miR-137 specifically in Hcrt neurons resulted in Hcrt upregulation, longer episodes of wakefulness, and significantly longer wake bouts in the first 4 h of the active phase. IL-13 stimulation upregulated endogenous miR-137, while Hcrt mRNA decreased both in vitro and in vivo. Furthermore, knockdown of miR-137 in zebrafish substantially increased wakefulness. Finally, we show that in humans, the MIR137 locus is genetically associated with sleep duration. In conclusion, these results show that an evolutionarily conserved miR-137:Hcrt interaction is involved in sleep–wake regulation.

The molecular mechanisms of sleep cycle integration at the beginning and the end of the inactive period are not clear. Sleep cycles with a predominance of deep slow-wave sleep (SWS) seem to be associated with accelerated protein synthesis in the brain. The inducible Hsp70 chaperone corrects protein conformational changes and has protective properties. This research explores (1) whether the Hspa1 gene encoding Hsp70 protein activates during the daily rapid-eye-movement sleep (REMS) maximum, and (2) whether a lower daily deep SWS maximum affects the Hspa1 expression level during the subsequent REMS. Combining polysomnography in male Wistar rats, RT-qPCR, and Western blotting, we reveal a three-fold Hspa1 upregulation in the nucleus reticularis pontis oralis, which regulates REMS. Hspa1 expression increases during the daily REMS maximum, 5-7 h after the natural peak of deep SWS. Using short-term selective REMS deprivation, we demonstrate that REMS rebound after deprivation exceeds the natural daily maximum, but it is not accompanied by Hspa1 upregulation. The results suggest that a high proportion of deep SWS, usually observed after sleep onset, is a necessary condition for Hspa1 upregulation during subsequent REMS. The data obtained can inform the understanding of the molecular mechanisms integrating SWS and REMS and key biological function(s) of sleep.

Objective: This study (1) examined pubertal development in relation to actigraphy-assessed sleep in twin children, and tested whether associations differed by child race and gender, (2) modeled genetic and environmental influences on pubertal development and sleep indicators, and (3) examined genetic and environmental influences on the covariation of puberty and sleep., Design: The classic twin design was used to examine genetic and environmental contributions to puberty and sleep and their associations., Setting: Data were collected from community-dwelling urban and rural families of twins in the southwestern U.S., Participants: The racially and socioeconomically diverse sample included 596 twin children (M age  = 8.41, SD = 0.69; 51.7% female; 66.3% white; 33.7% Hispanic; 170 monozygotic, 236 same-sex dizygotic, 188 opposite-sex dizygotic)., Measurements: Pubertal development was assessed via parent report. Children wore actigraph watches for 7 nights (M = 6.81, SD = 0.67) to capture sleep duration, efficiency, midpoint, onset latency, and duration variability., Results: In contrast to extant literature with older youth, more advanced pubertal development was associated with longer sleep durations in Hispanic and white girls and higher sleep efficiency in white girls, though Hispanic girls demonstrated later sleep midpoints. Pubertal development was moderately heritable and there was a genetic influence on the covariance between puberty and sleep indicators., Conclusions: This was the first study to examine the genetic and environmental influences on the covariation between puberty and sleep, and found genetic underpinnings between pubertal development and actigraphy-assessed sleep duration and efficiency, though sleep and puberty were almost entirely independent in twins at this age., (Copyright © 2021 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Background: CLOCK 3111T/C has been shown to be closely associated with morningness-eveningness, such as sleep-wake rhythms in healthy humans. However, previous studies examined the physical activity (PA) in a single day, and no study has investigated the relationships between CLOCK 3111T/C polymorphism and PA for an entire week. It was hypothesized that the CLOCK 3111T/C polymorphism might be associated with diurnal PA patterns, especially on the weekends., Methods: Eighty-one university students (male, n = 14; female, n = 67; age, 20.4 ± 2.9 years) wore a digital accelerometer for 7 successive days, including the weekend, to collect hour-by-hour objectively-measured PA. CLOCK 3111T/C polymorphism was assessed using the oral mucosa. During the study, participants recorded their wake time and bedtime each day. Furthermore, lifestyle-related variables (i.e. morningness-eveningness, habitual meal and sleep timings) were collected using questionnaires. Linear mixed-effects models assessed the association of polymorphism (TT carriers vs. TC+CC carriers) with wake time and bedtime as well as daily PA throughout the week (time)., Results: TT carriers had an earlier wake time (weekly mean: 44 min [95% CI, -82 to -5 min], time interaction: p = 0.026) and bedtime (weekly mean: 30 min [95% CI, -61 min to - 15 s], time interaction: p = 0.048) than TC+CC carriers. Furthermore, TT carriers' wake time and bedtime on Saturday were significantly later than on other days (gene interaction: all p < 0.05). On Saturday, the hour-by-hour PA in TT carriers was significantly greater than that in TC+CC carriers (hourly mean 1.7 min [95% CI, 0.2 to 3.4 min], time: p < 0.001, group: p = 0.028, interaction: p = 0.155)., Conclusions: CLOCK 3111T/C polymorphism may be associated with objectively measured hour-by-hour PA only on Saturday. Academic/social obligations may mask the genetically determined biological rhythm of PA on weekdays., (Copyright © 2022. Published by Elsevier Inc.)

Objective: To examine the effects of sleep traits on glycated hemoglobin (HbA1c)., Research Design and Methods: This study triangulated evidence across multivariable regression (MVR) and one- (1SMR) and two-sample Mendelian randomization (2SMR) including sensitivity analyses on the effects of five self-reported sleep traits (i.e., insomnia symptoms [difficulty initiating or maintaining sleep], sleep duration, daytime sleepiness, napping, and chronotype) on HbA1c (in SD units) in adults of European ancestry from the UK Biobank (for MVR and 1SMR analyses) (n = 336,999; mean [SD] age 57 [8] years; 54% female) and in the genome-wide association studies from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) (for 2SMR analysis) (n = 46,368; 53 [11] years; 52% female)., Results: Across MVR, 1SMR, 2SMR, and their sensitivity analyses, we found a higher frequency of insomnia symptoms (usually vs. sometimes or rarely/never) was associated with higher HbA1c (MVR 0.05 SD units [95% CI 0.04-0.06]; 1SMR 0.52 [0.42-0.63]; 2SMR 0.24 [0.11-0.36]). Associations remained, but point estimates were somewhat attenuated after excluding participants with diabetes. For other sleep traits, there was less consistency across methods, with some but not all providing evidence of an effect., Conclusions: Our results suggest that frequent insomnia symptoms cause higher HbA1c levels and, by implication, that insomnia has a causal role in type 2 diabetes. These findings could have important implications for developing and evaluating strategies that improve sleep habits to reduce hyperglycemia and prevent diabetes., (© 2022 by the American Diabetes Association.)

Genetic factors are surmised to regulate sleep as evidenced by the heritability of sleep traits, specific genetic polymorphisms of these traits, and familial sleep disorders. Sleep is also a very complex behavior that is regulated by circadian rhythm, homeostatic drive, and other processes. All these processes appear to have genetic factors; however, we still cannot elucidate sleep genes. Recent studies in humans and animal models have uncovered some genetic factors underlying sleep disturbances. In this review, we present an overview of genetical regulation of sleep and genetic factors underlying several sleep disturbances., Competing Interests: Disclosure The author has nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Study Objectives: The neurotrophin brain-derived neurotrophic factor (BDNF) is hypothesized to be a molecular mediator of mammalian sleep homeostasis. This hypothesis is supported by correlational findings and results obtained from pharmacology. BDNF binds with high affinity to the membrane-bound receptor Neurotrophin Tyrosine Kinase Receptor B (NtrkB), which triggers several intracellular signaling cascades. It is therefore possible that BDNF's role in sleep homeostasis is mediated via NtrkB. We examined this hypothesis using a chemical-genetic technique that allows for rapid and selective inhibition of NtrkB in vivo., Methods: We used mutant mice bearing a point mutation in the NtrkB that allows for selective and reversible inactivation in the presence of a small binding molecule (1-NM-PP1). Using a crossover design, we determined the effects of NtrkB inhibition on baseline sleep architecture and sleep homeostasis., Results: We find that NtrkB inhibition reduced rapid eye movement (REM) sleep time and changed state transitions but had no effect on sleep homeostasis., Conclusions: These findings suggest that BDNF-NtrkB receptor signaling has subtle roles in sleep architecture, but no role in sleep homeostasis., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Significant alterations in sleep duration and/or quality of sleep become more pronounced as people get older. Poor sleep in elderly people is associated with adverse health outcomes and cellular aging. We examined the relationship between telomere length (TL) and sleep duration, Health Promotion Index (HPI), and tested whether the presence of Apolipoprotein-E4 (ApoE-ε4) allele affects both sleep and TL. The present study was carried out in 174 healthy participants (21% male; mean age 53.79 years) from South Australia. Lymphocyte TL was measured by real-time quantitative PCR (qPCR) and ApoE genotype was determined by TaqMan assay. HPI was calculated from a questionnaire regarding 8 lifestyle habits, including sleeping hours. Multivariate regression analysis was used to establish these associations adjusted for specified confounders. TL was found to be inversely associated with age (r = -0.199; p = .008) and body mass index (r = -0.121; p = .11), and was significantly shorter in participants who slept for less than 7 hours (p = .001) relative to those sleeping ≥7 hours. TL was positively correlated with HPI (r = 0.195; p = .009). ApoE-ε4 allele carriers who slept for less than 7 hours had shortest TL (p = .01) compared to noncarriers. Plasma soluble receptor for advanced glycation end product (sRAGE) level was significantly (p = .001) lower in individuals who sleep less than 7 hours and ApoE-ε4 carriers. Our results suggest that inadequate sleep duration or poor HPI is associated with shorter TL in cognitively normal people and that carriage of APOE-ε4 genotype may influence the extent of these effects., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Occupational stress is associated with sleep quality among workers and the human variable number tandem repeat (VNTR) polymorphism of the period circadian regulator 3 (PER3) gene relates to sleep-wake regulation. The main aims of the present study were to examine the effects of PER3 VNTR genotypes, occupational stress, and their interactions on sleep quality. A cross-sectional study was conducted and 729 workers were recruited in Sichuan. Sleep quality were assessed using the Pittsburgh Sleep Quality Index. Occupational stress was measured using the Generic Job Stress Questionnaire. PER3 genotypes were determined with polymerase chain reaction. High and medium occupational stress were linked to a higher risk of poor sleep quality than low levels. Unconditional logistic regression indicated that PER3 genotype was significantly associated with sleep quality, and an increased risk of poor sleep of >1.5-times was observed in those with the allele 5 compared to allele 4. The 5/5 genotype was associated with both sleep latency and sleep duration. Crossover analysis showed an occupational stress × PER3 interaction. Compared to subjects with both low and medium occupational stress and 4/4 + 4/5 genotype, those with both high occupational stress and 5/5 genotype had a higher risk of poor sleep quality. Stratified logistic analyses found that compared with low and medium occupational stress, high occupational stress increased the risk of poor sleep by more than five-times in 5/5 genotype carriers. Occupational stress and PER3 genotype had both separate and combined effects on poor sleep quality of workers. The results suggest that occupational stress may increase the risk of poor sleep quality through interaction with the PER3 gene polymorphism., (© 2021 European Sleep Research Society.)

Introduction: Sleep insufficiency or decreased quality have been associated with Alzheimer's disease (AD) already in its preclinical stages. Whether such traits are also present in rodent models of the disease has been poorly addressed, somewhat disabling the preclinical exploration of sleep-based therapeutic interventions for AD., Methods: We investigated age-dependent sleep-wake phenotype of a widely used mouse model of AD, the Tg2576 line. We implanted electroencephalography/electromyography headpieces into 6-month-old (plaque-free, n = 10) and 11-month-old (moderate plaque-burdened, n = 10) Tg2576 mice and age-matched wild-type (WT, 6 months old n = 10, 11 months old n = 10) mice and recorded vigilance states for 24 h., Results: Tg2576 mice exhibited significantly increased wakefulness and decreased non-rapid eye movement sleep over a 24-h period compared to WT mice at 6 but not at 11 months of age. Concomitantly, power in the delta frequency was decreased in 6-month old Tg2576 mice in comparison to age-matched WT controls, rendering a reduced slow-wave energy phenotype in the young mutants. Lack of genotype-related differences over 24 h in the overall sleep-wake phenotype at 11 months of age appears to be the result of changes in sleep-wake characteristics accompanying the healthy aging of WT mice., Conclusion: Therefore, our results indicate that at the plaque-free disease stage, diminished sleep quality is present in Tg2576 mice which resembles aged healthy controls, suggesting an early-onset of sleep-wake deterioration in murine AD. Whether such disturbances in the natural patterns of sleep could in turn worsen disease progression warrants further exploration., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: Until now, both cross-sectional and longitudinal studies have identified controversial findings about the association between daytime napping and Alzheimer's disease (AD) or cognitive decline. Therefore, it remains unclear about the causal association between daytime napping and AD or cognitive decline., Objective: We aim to investigate the causal association between daytime napping and AD., Methods: Here, we conduct a bidirectional Mendelian randomization (MR) analysis to investigate the causal association between daytime napping and AD using large-scale GWAS datasets from daytime napping including 452,633 individuals of European ancestry and AD including 35,274 AD and 59,163 controls of European ancestry. A total of five MR methods are selected including inverse-variance weighted (IVW), weighted median, MR-Egger, MR-PRESSO, and contamination mixture method., Results: MR analysis highlights significant causal association of AD with daytime napping using IVW (beta = -0.006, 95% CI [-0.009, -0.002], p = 2.00E-03), but no significant causal association of daytime napping with AD using IVW (OR = 0.76, 95% CI 0.53-1.10, p = 1.40E-01)., Conclusion: Our bidirectional MR analysis demonstrates the causal effect of AD on daytime napping. However, there is no causal effect of daytime napping on AD. Our current findings are consistent with recent evidence from other MR studies that highlight little evidence supporting a causal effect of sleep traits on AD and support the causal effect of AD on sleep traits.

Sleep problems have been associated with cognition, both cross-sectionally and longitudinally. Specific genes have been also associated with both sleep regulation and cognition. In a large group of older non-demented adults, we aimed to (a) validate the association between Sleep Polygenic Risk Score (Sleep PRS) and self-reported sleep duration, and (b) examine the association between Sleep PRS and cognitive changes in a three-year follow-up. Participants were drawn from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). A structured, in-person interview, consisting of a medical history report and physical examination, was conducted for each participant during each of the visits (baseline and first follow-up). In total, 1376 participants were included, having all demographic, genetic, and cognitive data, out of which, 688 had at least one follow-up visit. In addition, an extensive neuropsychological assessment examining five cognitive domains (memory, visuo-spatial ability, attention/speed of processing, executive function, and language) was administered. A PRS for sleep duration was created based on previously published, genome-wide association study meta-analysis results. In order to assess the relationship between the Sleep PRS and the rate of cognitive change, we used generalized estimating equations analyses. Age, sex, education, ApolipoproteinE-ε4 genotype status, and specific principal components were used as covariates. On a further analysis, sleep medication was used as a further covariate. Results validated the association between Sleep PRS and self-reported sleep duration (B = 1.173, E-6, p = 0.001). Further, in the longitudinal analyses, significant associations were indicated between increased Sleep PRS and decreased visuo-spatial ability trajectories, in both the unadjusted (B = -1305.220, p = 0.018) and the adjusted for the covariates model (B = -1273.59, p = 0.031). Similarly, after adding sleep medication as a covariate (B = -1372.46, p = 0.019), none of the associations between Sleep PRS and the remaining cognitive domains were significant. PRS indicating longer sleep duration was associated with differential rates of cognitive decline over time in a group of non-demented older adults. Common genetic variants may influence the association between sleep duration and healthy aging/cognitive health.

BACKGROUNDTight relationships between sleep quality, cognition, and amyloid-β (Aβ) accumulation, a hallmark of Alzheimer's disease (AD) neuropathology, have been shown. Sleep arousals become more prevalent with aging and are considered to reflect poorer sleep quality. However, heterogeneity in arousals has been suggested while their associations with Aβ and cognition are not established.METHODSWe recorded undisturbed night-time sleep with EEG in 101 healthy individuals aged 50-70 years, devoid of cognitive and sleep disorders. We classified spontaneous arousals according to their association with muscular tone increase (M+/M-) and sleep stage transition (T+/T-). We assessed cortical Aβ burden over earliest affected regions via PET imaging and assessed cognition via neuropsychological testing.RESULTSArousal types differed in their oscillatory composition in θ (4-8 Hz) and β (16-30 Hz) EEG bands. Furthermore, T+M- arousals, interrupting sleep continuity, were positively linked to Aβ burden (P = 0.0053, R²β* = 0.08). By contrast, more prevalent T-M+ arousals, upholding sleep continuity, were associated with lower Aβ burden (P = 0.0003, R²β* = 0.13), and better cognition, particularly over the attentional domain (P < 0.05, R²β* ≥ 0.04).CONCLUSIONContrasting with what is commonly accepted, we provide empirical evidence that arousals are diverse and differently associated with early AD-related neuropathology and cognition. This suggests that sleep arousals, and their coalescence with other brain oscillations during sleep, may actively contribute to the beneficial functions of sleep and constitute markers of favorable brain and cognitive health trajectories.TRIAL REGISTRATIONEudraCT 2016-001436-35.FUNDINGFRS-FNRS Belgium (FRSM 3.4516.11), Actions de Recherche Concertées Fédération Wallonie-Bruxelles (SLEEPDEM 17/27-09), ULiège, and European Regional Development Fund (Radiomed Project).

Although many genes are known to influence sleep, when and how they impact sleep-regulatory circuits remain ill-defined. Here, we show that insomniac ( inc ), a conserved adaptor for the autism-associated Cul3 ubiquitin ligase, acts in a restricted period of neuronal development to impact sleep in adult Drosophila . The loss of inc causes structural and functional alterations within the mushroom body (MB), a center for sensory integration, associative learning, and sleep regulation. In inc mutants, MB neurons are produced in excess, develop anatomical defects that impede circuit assembly, and are unable to promote sleep when activated in adulthood. Our findings link neurogenesis and postmitotic development of sleep-regulatory neurons to their adult function and suggest that developmental perturbations of circuits that couple sensory inputs and sleep may underlie sleep dysfunction in neurodevelopmental disorders., Competing Interests: QL, HJ, KL, AL, NS No competing interests declared, (© 2021, Li et al.)

As organisms age, their resistance to stress decreases while their risk of disease increases. This can be shown in patients with Werner syndrome (WS), which is a genetic disease characterized by accelerated aging along with increased risk of cancer and metabolic disease. WS is caused by mutations in WRN , a gene involved in DNA replication and repair. Recent research has shown that WRN mutations contribute to multiple hallmarks of aging including genomic instability, telomere attrition, and mitochondrial dysfunction. However, questions remain regarding the onset and effect of stress on early aging. We used a fly model of WS ( WRNexo Δ ) to investigate stress response during different life stages and found that stress sensitivity varies according to age and stressor. While larvae and young WRNexo Δ adults are not sensitive to exogenous oxidative stress, high antioxidant activity suggests high levels of endogenous oxidative stress. WRNexo Δ adults are sensitive to stress caused by elevated temperature and starvation suggesting abnormalities in energy storage and a possible link to metabolic dysfunction in WS patients. We also observed higher levels of sleep in aged WRNexo Δ adults suggesting an additional adaptive mechanism to protect against age-related stress. We suggest that stress response in WRNexo Δ is multifaceted and evokes a systemic physiological response to protect against cellular damage. These data further validate WRNexo Δ flies as a WS model with which to study mechanisms of early aging and provide a foundation for development of treatments for WS and similar diseases.

The rs1344706 polymorphism in ZNF804A is robustly associated with schizophrenia and schizophrenia is, in turn, associated with abnormal non-rapid eye movement (NREM) sleep neurophysiology. To examine whether rs1344706 is associated with intermediate neurophysiological traits in the absence of disease, we assessed the relationship between genotype, sleep neurophysiology, and sleep-dependent memory consolidation in healthy participants. We recruited healthy adult males with no history of psychiatric disorder from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Participants were homozygous for either the schizophrenia-associated 'A' allele (N = 22) or the alternative 'C' allele (N = 18) at rs1344706. Actigraphy, polysomnography (PSG) and a motor sequence task (MST) were used to characterize daily activity patterns, sleep neurophysiology and sleep-dependent memory consolidation. Average MST learning and sleep-dependent performance improvements were similar across genotype groups, albeit more variable in the AA group. During sleep after learning, CC participants showed increased slow-wave (SW) and spindle amplitudes, plus augmented coupling of SW activity across recording electrodes. SW and spindles in those with the AA genotype were insensitive to learning, whilst SW coherence decreased following MST training. Accordingly, NREM neurophysiology robustly predicted the degree of overnight motor memory consolidation in CC carriers, but not in AA carriers. We describe evidence that rs1344706 polymorphism in ZNF804A is associated with changes in the coordinated neural network activity that supports offline information processing during sleep in a healthy population. These findings highlight the utility of sleep neurophysiology in mapping the impacts of schizophrenia-associated common genetic variants on neural circuit oscillations and function., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society.)

Elucidating the molecular pathways that regulate animal behavior such as sleep is essential for understanding how the brain works. However, to examine how a certain functional domain of protein is involved in animal behavior is challenging. Here, we present a protocol for inducing endogenous protein that lacks a specific functional domain using Cre-mediated allele modification in neurons followed by electroencephalogram/electromyogram (EEG/EMG) recording to study the role of kinases in sleep. This strategy is applicable to other gene targets or behaviors. For complete details on the use and execution of this protocol, please refer to Iwasaki et al. (2021)., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Many aspects of sleep are heritable, but only a few sleep-regulating genes have been reported. Here, we leverage mouse models to identify and confirm a previously unreported gene affecting sleep duration-dihydropyrimidine dehydrogenase (Dpyd). Using activity patterns to quantify sleep in 325 Diversity Outbred (DO) mice-a population with high genetic and phenotypic heterogeneity-a linkage peak for total sleep in the active lights off period was identified on chromosome 3 (LOD score = 7.14). Mice with the PWK/PhJ ancestral haplotype at this location demonstrated markedly reduced sleep. Among the genes within the linkage region, available RNA sequencing data in an independent sample of DO mice supported a highly significant expression quantitative trait locus for Dpyd, wherein reduced expression was associated with the PWK/PhJ allele. Validation studies were performed using activity monitoring and EEG/EMG recording in Collaborative Cross mouse strains with and without the PWK/PhJ haplotype at this location, as well as EEG and EMG recording of sleep and wake in Dpyd knockout mice and wild-type littermate controls. Mice lacking Dpyd had 78.4 min less sleep during the lights-off period than wild-type mice (p = 0.007; Cohen's d = -0.94). There was no difference in other measured behaviors in knockout mice, including assays evaluating cognitive-, social-, and affective-disorder-related behaviors. Dpyd encodes the rate-limiting enzyme in the metabolic pathway that catabolizes uracil and thymidine to β-alanine, an inhibitory neurotransmitter. Thus, data support β-alanine as a neurotransmitter that promotes sleep in mice., Competing Interests: Declaration of interests A.I.P. is The John L. Miclot Professor of Medicine at the University of Pennsylvania; funds for this endowment were provided by the Philips Respironics Foundation. G.A.C., E.J.C., and K.L.S. disclose that The Jackson Laboratory produces and sells a wide variety of mice for research, including Collaborative Cross and Diversity Outbred mice. The other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the shared genetic components, common pathways and causal relationship between ADHD and sleep-related phenotypes., Methods: We used the largest genome-wide association summary statistics available for attention-deficit/hyperactivity disorder (ADHD) and various sleep-related phenotypes (insomnia, napping, daytime dozing, snoring, ease getting up, daytime sleepiness, sleep duration and chronotype). We estimated the genomic correlation using cross-trait linkage disequilibrium score regression (LDSR) and investigated the potential common mechanisms using gene-based cross-trait metanalyses and functional enrichment analyses. The causal effect was estimated using two-sample Mendelian randomisation (TSMR), using the inverse variance weighted method as the main estimator., Results: A positive genomic correlation between insomnia, daytime napping, daytime dozing, snoring, daytime sleepiness, short and long sleep duration, and ADHD was observed. Insomnia, daytime sleepiness, and snoring shared genes with ADHD, that are involved in neurobiological functions and regulatory signalling pathways. The TSMR supported a causal effect of insomnia, daytime napping, and short sleep duration on ADHD, and of ADHD on long sleep duration and chronotype., Conclusion: Comorbidity between sleep phenotypes and ADHD may be mediated by common genetic factors that play an important role in neuronal signalling pathways. A causal effect of sleep disturbances and short sleep duration on ADHD reinforced their role as predictors of ADHD.

A number of genome-wide association studies have investigated sleep phenotypes and disorders in humans. However, the contribution of genetic variation to sleep problems in Japanese populations has remained unclear. Sleep-onset problems are the most common symptom of insomnia. Here, we examined the relationship between single nucleotide polymorphisms (SNPs) of BMAL1 (ARNTL1), CLOCK, CRY1, CRY2, and PER2, which are genes involved in the clock mechanism, and sleep-onset problems in a Japanese general population. This study included 1,397 subjects aged ≥ 40 years who participated in an annual health check-up in Yamagata Prefecture. A total of 80 SNPs of 5 circadian clock genes were analyzed. Multivariate logistic regression analyses identified variant rs11113179 in CRY1 and variants rs1026071 and rs1562438 in BMAL1 as genetic risk factors for sleep induction disorder. These findings suggest that CRY1 and BMAL1 polymorphisms are related to sleep-onset problems in a Japanese general population. However, none of the SNPs remained significant at a stringent level of multiple correction.

Introduction: Diurnal preferences have been linked to personality but often with mixed results. The present study examines the relationships between sleep timing (chronotype), diurnal preferences, and the Five-Factor Model of personality traits at the phenotypic and genetic level., Methods: Self- and informant-reports of the NEO Personality Inventory-3, self-reports of the Munich Chronotype Questionnaire, and DNA samples were available for 2,515 Estonian adults (M age  = 45.76 years; 59% females). Genetic correlations were obtained through summary statistics of genome-wide association studies., Results: Results showed that higher Conscientiousness and lower Openness to Experience were significant predictors of earlier chronotype. At the level of facets, we found that more straightforward (A2) and excitement-seeking (E5), yet less self-disciplined (C5) people were more likely to have later chronotypes. The nuance-level Polypersonality score was correlated with chronotype at r = .28 (p < .001). Conscientiousness and Openness were genetically related with diurnal preferences. The polygenic score for morningness-eveningness significantly predicted the Polypersonality score., Conclusion: Phenotypic measures of chronotype and personality showed significant associations at all three of levels of the personality hierarchy. Our findings indicate that the relationship between personality and morningness-eveningness is partly due to genetic factors. Future studies are necessary to further refine the relationship., (© 2021 The Authors. Journal of Personality published by Wiley Periodicals LLC.)

The hippocampus is essential for consolidating transient experiences into long-lasting memories. Memory consolidation is facilitated by postlearning sleep, although the underlying cellular mechanisms are largely unknown. We took an unbiased approach to this question by using a mouse model of hippocampally mediated, sleep-dependent memory consolidation (contextual fear memory). Because synaptic plasticity is associated with changes to both neuronal cell membranes (e.g., receptors) and cytosol (e.g., cytoskeletal elements), we characterized how these cell compartments are affected by learning and subsequent sleep or sleep deprivation (SD). Translating ribosome affinity purification was used to profile ribosome-associated RNAs in different subcellular compartments (cytosol and membrane) and in different cell populations (whole hippocampus, Camk2a+ neurons, or highly active neurons with phosphorylated ribosomal subunit S6 [pS6+]). We examined how transcript profiles change as a function of sleep versus SD and prior learning (contextual fear conditioning; CFC). While sleep loss altered many cytosolic ribosomal transcripts, CFC altered almost none, and CFC-driven changes were occluded by subsequent SD. In striking contrast, SD altered few transcripts on membrane-bound (MB) ribosomes, while learning altered many more (including long non-coding RNAs [lncRNAs]). The cellular pathways most affected by CFC were involved in structural remodeling. Comparisons of post-CFC MB transcript profiles between sleeping and SD mice implicated changes in cellular metabolism in Camk2a+ neurons and protein synthesis in highly active pS6+ (putative "engram") neurons as biological processes disrupted by SD. These findings provide insights into how learning affects hippocampal neurons and suggest that the effects of SD on memory consolidation are cell type and subcellular compartment specific., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Study Objectives: A critical role linking sleep with memory decay and β-amyloid (Aβ) accumulation, two markers of Alzheimer's disease (AD) pathology, may be played by hippocampal integrity. We tested the hypotheses that worse self-reported sleep relates to decline in memory and intra-hippocampal microstructure, including in the presence of Aβ., Methods: Two-hundred and forty-three cognitively healthy participants, aged 19-81 years, completed the Pittsburgh Sleep Quality Index once, and two diffusion tensor imaging sessions, on average 3 years apart, allowing measures of decline in intra-hippocampal microstructure as indexed by increased mean diffusivity. We measured memory decay at each imaging session using verbal delayed recall. One session of positron emission tomography, in 108 participants above 44 years of age, yielded 23 Aβ positive. Genotyping enabled control for APOE ε4 status, and polygenic scores for sleep and AD, respectively., Results: Worse global sleep quality and sleep efficiency related to more rapid reduction of hippocampal microstructure over time. Focusing on efficiency (the percentage of time in bed at night spent asleep), the relation was stronger in presence of Aβ accumulation, and hippocampal integrity decline mediated the relation with memory decay. The results were not explained by genetic risk for sleep efficiency or AD., Conclusions: Worse sleep efficiency related to decline in hippocampal microstructure, especially in the presence of Aβ accumulation, and Aβ might link poor sleep and memory decay. As genetic risk did not account for the associations, poor sleep efficiency might constitute a risk marker for AD, although the driving causal mechanisms remain unknown., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society.)

Background: A range of sleep disturbances are commonly experienced by patients with psychiatric disorders, and genome-wide genetic analyses have shown some significant genetic correlations between these traits. Here, we applied novel statistical genetic methodologies to better characterize the potential shared genetic architecture between sleep-related phenotypes and psychiatric disorders., Methods: Using the MiXeR method, which can estimate polygenic overlap beyond genetic correlation, the shared genetic architecture between major psychiatric disorders (bipolar disorder [N = 51,710], depression [N = 480,359], and schizophrenia [N = 77,096]) and sleep-related phenotypes (chronotype [N = 449,734], insomnia [N = 386,533] and sleep duration [N = 446,118]) were quantified on the basis of genetic summary statistics. Furthermore, the conditional/conjunctional false discovery rate framework was used to identify specific shared loci between these phenotypes, for which positional and functional annotation were conducted with FUMA., Results: Extensive genetic overlap between the sleep-related phenotypes and bipolar disorder (63%-77%), depression (76%-79%), and schizophrenia (64%-79%) was identified, with moderate levels of congruence between most investigated traits (47%-58%). Specific shared loci were identified for all bivariate analyses, and a subset of 70 credible genes were mapped to these shared loci., Conclusions: The current results provide evidence for substantial polygenic overlap between psychiatric disorders and sleep-related phenotypes, beyond genetic correlation (|r g | = 0.02 to 0.42). Moderate congruency within the shared genetic components suggests a complex genetic relationship and potential subgroups with higher or lower genetic concordance. This work provides new insights and understanding of the shared genetic etiology of sleep-related phenotypes and psychiatric disorders and highlights new opportunities and avenues for future investigation., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

NRXN1 is involved in synaptogenesis and have been implicated in Autism spectrum disorders. However, many rare inherited missense variants of NRXN1 have not been thoroughly evaluated. Here, functional analyses in vitro and in Drosophila of three NRXN1 missense mutations, Y282H, L893V, and I1135V identified in ASD patients in our previous study were performed. Our results showed these three mutations interfered protein degradation compared with NRXN1-WT protein. Expressing human NRXN1 in Drosophila could lead to abnormal circadian rhythm and sleep behavior, and three mutated proteins caused milder phenotypes, indicating the mutations may change the function of NRXN1 slightly. These findings highlight the functional role of rare NRXN1 missense variants identified in autism patients, and provide clues for us to better understand the pathogenesis of abnormal circadian rhythm and sleep behavior of other organisms, including humans., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Late diurnal preference has been linked to poorer mental health outcomes, but the understanding of the causal role of diurnal preference on mental health and wellbeing is currently limited. Late diurnal preference is often associated with circadian misalignment (a mismatch between the timing of the endogenous circadian system and behavioural rhythms), so that evening people live more frequently against their internal clock. This study aims to quantify the causal contribution of diurnal preference on mental health outcomes, including anxiety, depression and general wellbeing and test the hypothesis that more misaligned individuals have poorer mental health and wellbeing using an actigraphy-based measure of circadian misalignment. Multiple Mendelian Randomisation (MR) approaches were used to test causal pathways between diurnal preference and seven well-validated mental health and wellbeing outcomes in up to 451,025 individuals. In addition, observational analyses tested the association between a novel, objective measure of behavioural misalignment (Composite Phase Deviation, CPD) and seven mental health and wellbeing outcomes. Using genetic instruments identified in the largest GWAS for diurnal preference, we provide robust evidence that early diurnal preference is protective for depression and improves wellbeing. For example, using one-sample MR, a twofold higher genetic liability of morningness was associated with lower odds of depressive symptoms (OR: 0.92, 95% CI: 0.88, 0.97). It is possible that behavioural factors including circadian misalignment may contribute in the chronotype depression relationship, but further work is needed to confirm these findings., (© 2021. The Author(s).)

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P joint  < 5 × 10 -8 ), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P int  < 5 × 10 -8 ). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P int  = 2 × 10 -6 ). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P int  < 10 -3 ). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

At least one-third of adults in the United States experience intermittent hypoxia (IH) due to health or living conditions. The majority of these adults suffer with sleep breathing conditions and associated circadian rhythm disorders. The impact of IH on the circadian clock is not well characterized. In the current study, we used an IH mouse model to understand the impact of IH on the circadian gene expression of the canonical clock genes in the central (the brain) and peripheral (the liver) tissues. Gene expression was measured using a Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). CircaCompare was used to evaluate the differential rhythmicity between normoxia and IH. Our observations suggested that the circadian clock in the liver was less sensitive to IH compared to the circadian clock in the brain.

Considerable recent advancements in elucidating the genetic architecture of sleep traits and sleep disorders may provide insight into the relationship between sleep and obesity. Despite the involvement of the circadian clock in sleep and metabolism, few shared genes, including FTO , were implicated in genome-wide association studies (GWASs) of sleep and obesity. Polygenic scores composed of signals from GWASs of sleep traits show largely null associations with obesity, suggesting lead variants are unique to sleep. Modest genome-wide genetic correlations are observed between many sleep traits and obesity and are largest for snoring. Notably, U-shaped positive genetic correlations with body mass index (BMI) exist for both short and long sleep durations. Findings from Mendelian randomization suggest robust causal effects of insomnia on higher BMI and, conversely, of higher BMI on snoring and daytime sleepiness. In addition, bidirectional effects between sleep duration and daytime napping with obesity may also exist. Limited gene-sleep interaction studies suggest that achieving favorable sleep, as part of a healthy lifestyle, may attenuate genetic predisposition to obesity,but whether these improvements produce clinically meaningful reductions in obesity risk remains unclear. Investigations of the genetic link between sleep and obesity for sleep disorders other than insomnia and in populations of non-European ancestry are currently limited.

Epidemiological and interventional research has highlighted sleep as a potentially modifiable risk factor associated with poor physical and mental health. Emerging evidence from (behavioral) genetic research also shows that sleep characteristics are under strong genetic control. With this study we aimed to meta-analyze the literature in this area to quantify the heritability of sleep duration and sleep quality in the general population. We conducted a systematic literature search in five online databases on January 24th 2020. Two authors independently screened 5644 abstracts, and 160 complete articles for the inclusion criteria of twin studies from the general population reporting heritability statistics on sleep duration and/or quality, and written in English. We ultimately included 23 papers (19 independent samples: 45,328 twins between 6 mo and 88 y) for sleep duration, and 13 papers (10 independent samples: 39,020 twins between 16 and 95 y) for sleep quality. Collectively, we showed that 46% of the variability in sleep duration and 44% of the variability in sleep quality is genetically determined. The remaining variation in the sleep characteristics can mostly be attributed to the unique environment the twins experience, although the shared environment seemed to play a role for the variability of childhood sleep duration. Meta-analyzed heritability estimates for sleep duration, however, varied substantially with age (17% infancy, 20-52% childhood, 69% adolescence and 42-45% adulthood) and reporter (8% parent-report, 38-52% self-report). Heritability estimates for actigraphic and Polysomnography (PSG)-estimated sleep were based on few small samples, warranting more research. Our findings highlight the importance of considering genetic influences when aiming to understand the underlying mechanisms contributing to the trajectories of sleep patterns across the lifespan., Competing Interests: Disclosure The work was funded by NWA Startimpuls Royal Netherlands Academy of Arts and Sciences 2017 Grant (AZ/3137) and by the European Research Council grant ERC-2014-AdG-671084 INSOMNIA., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The causal nature of the sleep-obesity association is unclear. To control for potential confounding by genes and shared environment, we studied monozygotic twin pairs discordant for body mass index (BMI). First, we investigated sleep in relation to BMI. Second, we examined associations of objective and subjective sleep duration and sleep debt (objective or subjective sleep duration minus subjective sleep need) with eating behaviors and physical activity (PA)., Design: Cross-sectional study., Setting: Finnish twins in everyday life circumstances., Participants: Seventy-four healthy young adult monozygotic twin pairs, of whom 36 were BMI-discordant (∆BMI ≥ 3 kg/m 2 )., Measurements: Clinical measurements estimated BMI and body composition. Sleep, eating, and PA behaviors were measured by self-report and actigraphy., Results: Compared to co-twins with lower BMI, co-twins with higher BMI reported shorter sleep (P = .043), more snoring (P = .0093), and greater tiredness (P = .0013) and trended toward eveningness (P = .036). Actigraphy-measured sleep duration correlated highly within BMI-discordant twin pairs (r = 0.63, P = .004). Subjective sleep debt was consistently positively associated with disinhibited eating and binge eating, but not with BMI. Subjective and objective sleep debt had negative correlations with moderate-to-vigorous PA., Conclusions: Twins with higher BMI showed less favorable sleep characteristics than their co-twins with lower BMI. Subjective sleep debt is a potential target for intervention to reduce eating and PA behaviors that promote weight gain. Experimental studies could elucidate mechanisms underlying tiredness in individuals with higher BMI and investigate causal relationships between sleep debt, BMI, and lifestyle., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

During sleep, most animal species enter a state of reduced consciousness characterized by a marked sensory disconnect. Yet some processing of the external world must remain intact, given that a sleeping animal can be awoken by intense stimuli (for example, a loud noise or a bright light) or by soft but qualitatively salient stimuli (for example, the sound of a baby cooing or hearing one's own name 1-3 ). How does a sleeping brain retain the ability to process the quality of sensory information? Here we present a paradigm to study the functional underpinnings of sensory discrimination during sleep in Drosophila melanogaster. We show that sleeping vinegar flies, like humans, discern the quality of sensory stimuli and are more likely to wake up in response to salient stimuli. We also show that the salience of a stimulus during sleep can be modulated by internal states. We offer a prototypical blueprint detailing a circuit involved in this process and its modulation as evidence that the system can be used to explore the cellular underpinnings of how a sleeping brain experiences the world., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Gamma-aminobutyric acid type A (GABAA) receptors mainly mediate the effects of gamma-aminobutyric acid, which is the primary inhibitory neurotransmitter in the central nervous system. Abundant evidence suggests that GABAA receptors play a key role in sleep-regulating processes. No genetic association study has explored the relationships between GABAA receptor genes and sleep duration, sleep quality, and sleep timing in humans., Methods: We determined the association between single-nucleotide polymorphisms (SNPs) in the GABAA receptor genes GABRA1, GABRA2, GABRB3, GABRA5, and GABRG3 and sleep duration, sleep quality, and sleep timing in the Taiwan Biobank with a sample of 10,127 Taiwanese subjects. There were 10,142 subjects in the original study cohort. We excluded 15 subjects with a medication history of sedative-hypnotics., Results: Our data revealed an association of the GABRB3-GABRA5-GABRG3 gene cluster with sleep duration, which has not been previously identified: rs79333046 (beta = - 0.07; P = 1.21 × 10 -3 ) in GABRB3, rs189790076 (beta = 0.92; P = 1.04 × 10 -3 ) in GABRA5, and rs147619342 (beta = - 0.72; P = 3.97 × 10 -3 ) in GABRG3. The association between rs189790076 in GABRA5 and sleep duration remained significant after Bonferroni correction. A variant (rs12438141) in GABRB3 was also found to act as a potential expression quantitative trait locus. Additionally, we discovered interactions between variants in the GABRB3-GABRA5-GABRG3 gene cluster and lifestyle factors, such as tea and coffee consumption, smoking, and physical activity, that influenced sleep duration, although some interactions became nonsignificant after Bonferroni correction. We also found interactions among GABRB3, GABRA5, and GABRG3 that affected sleep duration. Furthermore, we identified an association of rs7165524 (beta = - 0.06; P = 2.20 × 10 -3 ) in GABRA5 with sleep quality and an association of rs79465949 (beta = - 0.12; P = 3.95 × 10 -3 ) in GABRB3 with sleep timing, although these associations became nonsignificant after Bonferroni correction. However, we detected no evidence of an association of individual SNPs in GABRA1 and GABRA2., Conclusions: Our results indicate that rs189790076 in GABRA5 and gene-gene interactions among GABRB3, GABRA5, and GABRG3 may contribute to sleep duration in the Taiwanese population., (© 2021. The Author(s).)

Social isolation and loneliness have potent effects on public health 1-4 . Research in social psychology suggests that compromised sleep quality is a key factor that links persistent loneliness to adverse health conditions 5,6 . Although experimental manipulations have been widely applied to studying the control of sleep and wakefulness in animal models, how normal sleep is perturbed by social isolation is unknown. Here we report that chronic, but not acute, social isolation reduces sleep in Drosophila. We use quantitative behavioural analysis and transcriptome profiling to differentiate between brain states associated with acute and chronic social isolation. Although the flies had uninterrupted access to food, chronic social isolation altered the expression of metabolic genes and induced a brain state that signals starvation. Chronically isolated animals exhibit sleep loss accompanied by overconsumption of food, which resonates with anecdotal findings of loneliness-associated hyperphagia in humans. Chronic social isolation reduces sleep and promotes feeding through neural activities in the peptidergic fan-shaped body columnar neurons of the fly. Artificial activation of these neurons causes misperception of acute social isolation as chronic social isolation and thereby results in sleep loss and increased feeding. These results present a mechanistic link between chronic social isolation, metabolism, and sleep, addressing a long-standing call for animal models focused on loneliness 7 ., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)