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Genome-wide identification and functional validation of the WW domain containing oxidoreductase gene associated with sleep duration.

Individual differences in sleep duration have been reported, and genetic components of sleep duration have been identified showing various heritability. To identify genetic variants that contribute to sleep duration, we conducted a human genome-wide identification on sleep duration and performed confirmatory experiments using a Drosophila model. Genome-wide association study in human was analyzed to determine the association of the genetic variants with self-aware sleep duration from two community-based cohort, Ansan (cohort 1, n&#x2009;=&#x2009;4635) and Ansung (cohort 2, n&#x2009;=&#x2009;4205), recruited from the Korean Genome and Epidemiology Study. Individual single nucleotide variants (rs16948804 and rs4887991) in the WW domain containing oxidoreductase (WWOX) gene were associated with self-aware sleep duration in human (p-values, 1.11&#x2009;&#xd7;&#x2009;10-&#x2009;7 and 2.05&#x2009;&#xd7;&#x2009;10-&#x2009;7, retrospectively). To examine the functional relevance of the WWOX gene identified in the genome-wide association study, we analyzed the sleep duration of Drosophila loss-of-function mutants. The deletion of Wwox in flies reduced sleep duration and quality with average bout length during daytime and increased night-time sleep duration (all of p-values&#x2009;<&#x2009;0.01). Our findings suggested that WWOX expression is associated with sleep duration in both humans and Drosophila and genetic factors play a role in inter-individual variability in sleep characteristics.

Humans

Handedness and sleep duration.

The differences in habitual sleep duration and absolute deviations in habitual sleep duration from the normative mean between 60 left-, 36 mixed- and 125 right-handed college students were tested. It was found that mixed-handers tend to sleep less and as a group show significantly greater deviations in habitual sleep durations than either left- or right-handers. The heuristic value of this relationship for future research was discussed briefly.

Functional Laterality

Genetic risk scores, perceived neighborhood disorder, and sleep duration.

STUDY OBJECTIVES: Most studies of neighborhood context and sleep health emphasize direct effects and fail to account for the role of genetics. In this paper, we draw on the socioecological model to examine the interplay of genetics, neighborhood context, and sleep health. We specifically examine the independent and joint effects of genetic risk scores (GRS) and perceived neighborhood disorder on sleep duration. METHODS: We combine genomic and cross-sectional survey data from the All of Us Research Program, a non-probability sample of 22&#x2009;575 adults of European ancestry living in the United States. We use the sleep duration-increasing risk allele count for 78 genome-wide single nucleotide polymorphisms (SNPs) to construct weighted genetic risk scores. Our analyses include an index of perceived neighborhood disorder and an objective measure of sleep duration based on wrist actigraphy. RESULTS: Genetic risk scores are inversely associated with neighborhood disorder, positively associated with continuous sleep duration, and inversely associated with the odds of short sleep. Neighborhood disorder is inversely associated with continuous sleep duration and positively associated with the odds of short and long sleep. The association between genetic risk scores and sleep duration (continuous and categorical) is invariant across levels of neighborhood disorder. CONCLUSIONS: Our analyses confirm the independent direct effects of genetic risk scores and neighborhood disorder on sleep duration. Our findings extend the socioecological model by assessing the role of genetics in the study of neighborhood context and sleep health. Although we observed a gene-environment correlation between genetic risk scores and perceived neighborhood disorder, there was little indication of genetic confounding and no evidence of gene-environment interaction.

Humans

Polygenic score for sleep duration in relation to the risk of Alzheimer's disease: results from the UK biobank.

Studies have suggested that sleep duration may be associated with Alzheimer's disease risk; however, findings based on self-reported sleep duration are likely to be influenced by reverse causation and residual confounding bias. We derived weights for genetic variants associated with wearable-derived sleep duration using the LDpred2-auto method in 77,770 white British participants from the UK Biobank, following the generation of new genome-wide association summary statistics. We then used these weights to generate polygenic scores (PGSs) for the remaining 264,746 white British participants for the association analysis, independent of the sample used to develop PGS weights. We assessed the association of fifths between genetically predicted sleep duration and the risk of Alzheimer's disease (1,451 cases/264,746 individuals over a median 12.5&#x202f;years of follow-up). The PGS explained approximately 2% of the variation in device-measured sleep duration. Compared with individuals in the middle fifth of PGSs, those in the highest fifth (indicating approximately 15&#x202f;min/day longer sleep) had a lower risk of Alzheimer's disease (hazard ratio (HR)&#x202f;=&#x202f;0.79[95%CI, 0.67-0.94]). Our results indicate that genetic predisposition to relatively long sleep duration is associated with a lower Alzheimer's disease risk.

Alzheimer&#x2019;s disease

Causal Effects of Gut Microbiota on Morning Chronotype, Insomnia and Sleep Duration: A Two-Sample Mendelian Randomization Study.

BACKGROUND: The gut microbiota has been shown to be closely associated with brain function; however, whether it exerts a causal influence on sleep traits remains to be further explored. Mendelian randomization (MR) is an emerging epidemiological approach that uses whole-genome sequencing data to infer causal relationships. In this study, we conducted a two-sample MR analysis to investigate the causal effects of gut microbiota on three domains of sleep traits: morning chronotype, insomnia, and sleep duration. METHODS: Single nucleotide polymorphisms strongly associated with 196 gut microbiota taxa were selected as instrumental variables. Morning chronotype, insomnia, and sleep duration were used as outcomes. MR and sensitivity analyses were performed to assess the causal relationships between gut microbiota and sleep traits. RESULTS: Three taxa (Bifidobacteriales, Bifidobacteriaceae, and Bifidobacterium) were negatively associated with morning chronotype, while Tyzzerella 3 showed a positive causal effect on morning chronotype. Oscillibacter was negatively associated with insomnia, whereas four taxa (Negativicutes, Selenomonadales, the Clostridium innocuum group, and Lachnoclostridium) were identified as risk-increasing factors for insomnia. Lentisphaerae and Victivallaceae were positively associated with sleep duration. Actinobacteria and Alistipes had negative effects on long sleep duration, whereas Ruminiclostridium 6 was positively associated with long sleep duration. Four taxa (Victivallales, Anaerofilum, Lentisphaerae, and Lentisphaeria) were negatively associated with short sleep duration. CONCLUSIONS: Our findings suggest that specific gut microbiota taxa may be positively or negatively associated with sleep traits. These results offer new insights into the potential role of gut microbiota in sleep regulation and provide a basis for future studies aimed at understanding whether modulating microbial composition could influence sleep health.

Mendelian randomization

Self-reported consistency of normal habitual sleep durations of college students.

A relationship between hours of sleep/night and the consistency of this normal daily sleep duration was observed for 763 college students who had rated themselves as good sleepers with stable and fairly well established patterns of sleep. Congruent with a limited literature, these data suggest that shorter sleep durations are likely, for college students, to be relatively recently acquired patterns of sleep.

Circadian Rhythm

Behavioral and psychological correlates of a difference in chronic sleep duration.

The relationship between chronic differences in sleep duration and waking behaviors was explored by comparing two groups of 10 healthy male university students who regularly slept nocturnally for 7-8 h or for 9.5-10.5 h. Measurements were obtained of sublingual temperature, from a 45 min Wilkinson auditory vigilance task and a mood adjective check list 30 min after awakening in the morning, at midday ind in the early evening following an electroencephalographically recorded night of sleep. In both subject groups body temperature increased from morning to early evening, while misses on the vigilance task correspondingly declined during the day. The average daily level of oral temperature and performance were significantly lower in the 7-8 h (control) group than in the long sleepers. Positive mood states (Cheerful, Energetic, General Activation, High Activation) were significantly greater and negative affects (Anger-Hostility, Depression) significantly less in the long sleepers. As a result of the mean difference in total sleep time existing between groups control subjects averaged significantly less stage 2, and stage REM sleep. It was postulated that there were behavioral deficits in the control group attirbutable either to selective sleep stage deprivation or to the general consequence of reduced sleep per se or to both of these factors.

Adolescent

The impact of sleep duration on the incidence of new-onset chronic kidney disease in community-dwelling adults: a nationwide cohort study.

BACKGROUND: This research examined the association between sleep duration and new-onset chronic kidney disease (CKD) among community-dwelling middle-aged and elderly individuals in Korea. METHODS: This prospective cohort study utilized data from the Korean Genome and Epidemiology Study (KoGES) from 2001-2002 (baseline) to 2019-2020 (tenth follow-up visit). New-onset CKD was the primary outcome,&#xa0;defined as an estimated glomerular filtration rate <60&#x2009;mL/min/1.73 m2 or the proteinuria. Study populations were classified into six self-reported sleep length categories: <5h, 5h&#x2009;&#x2264; to <6h, 6h&#x2009;&#x2264;&#x2009;to <7h, 7h&#x2009;&#x2264; to &#x2264;8h, 8h&#x2009;<&#x2009;to <9h, and 9h/day &#x2264;. Cox proportional hazards models were used to ascertain the hazard ratios (HRs) and 95% confidence intervals (CIs) for CKD incidence across these categories. RESULTS: Over a median follow-up duration of 17.41&#x2009;years, CKD was identified in 551 (14.4%) of 3835 participants (mean age 48.7 &#xb1; 7.5&#x2009;years). After adjusting for confounding variables, a U-shaped relationship between sleep lengths and CKD was identified. Participants with insufficient (<5h) and excessive (9h &#x2264;) sleep length exhibited HRs for CKD incidence of 1.44 (1.09-1.89) and 1.85 (1.04-3.27), respectively, compared to individuals with normal sleep length (7h&#x2009;&#x2264;&#x2009;to &#x2264;8h). Age and sex differences were observed in the association between sleep length and CKD incidence. The association between sleep duration and new-onset CKD was significant only in participants aged 40 to 64&#x2009;years, with no significant association observed in individuals aged 65&#x2009;years and older. CONCLUSIONS: This research identified a relationship between the amount of sleep and CKD in Korean adults. Maintaining an appropriate sleep duration of 7-8&#x2009;h/day is important for preventing new-onset CKD.

Humans

Multi-clinic double-blind comparison of triazolam (Halcion) and placebo administered for 14 consecutive nights in outpatients with insomnia.

In this multi-clinic double-blind study, patients suffering from insomnia were treated with triazolam 0.5 mg (Halcion) or placebo for 14 days. Four investigators treated 239 patients, 122 on triazolam and 117 on placebo. Thirty-nine patients, 10 on triazolam and 29 on placebo, dropped out for ineffectiveness of the medication and 32 patients, 16 in each group, dropped out for side effects. Analysis of pooled efficacy data showed that triazolam was significantly better than placebo on all efficacy parameters measured, including how much the medication helped the patients sleep, onset of sleep, duration of sleep, duration compared to usual, number of nocturnal awakenings, and feeling of restfulness in the morning. Triazolam did not produce evidence of tolerance development after 2 weeks of treatment. The same variety of side effects occurred on each treatment and primarily included drowsiness, grogginess, headaches, impaired coordination nausea, and dizziness.

Adolescent

[Some indices of the activity of the brain in "rapid" sleep preceeded or not preceeded by delta-sleep].

In order to study the functional interaction between the delta sleep and the REM sleep some psychophysiological features of REM sleep were examined in REM-onset (without any preceding delta sleep--"early REM period") and in the REM period (REMP) terminating the normal sleep cycle (with the preceding delta sleep) of 92 daytime sleep attacks in 10 narcoleptic patients. Under these conditions the significant differences exist in the characteristics of the dream reports and in subjective estimations of sleep quality and duration. Sleep was evaluated as "superficial" and underestimations of sleep duration took place after an early REMP. Correct estimations of sleep duration and evaluations of sleep as "deep" dominated after REMP enging sleep cycles. The results obtained indicate the functional interaction between the delta sleep and REM sleep existing in the sleep cycle and largely determining the psychic content of the brain activity in the REM sleep.

Brain

Genetic Association Between Sleep Traits and Vertigo Risk: A Two-sample Bidirectional Mendelian Randomization Study.

BACKGROUND: Observational studies suggest the potential association between sleep traits and vertigo; however, causal evidence remains limited. OBJECTIVE: This study aimed to explore the relationship between genetically predicted sleep traits and vertigo with the Mendelian randomization (MR) method. METHODS: Instrumental variables for sleep traits (snoring, sleep duration, insomnia, daytime sleepiness, daytime napping, and chronotype) were adopted from genomewide association studies (GWAS) data of European ancestry from UK Biobank. The summary-level datasets of vertigo were retrieved from the GWAS of FinnGen. Inversevariance weighted (IVW) method was adopted as the main analysis. RESULTS: IVW analysis revealed a significant association between genetically predicted daytime napping (OR = 1.51, 95% CI =1.08-2.12, P = 0.016) and chronotype (OR = 1.13, 95% CI =1.01-1.26, P = 0.033), both of which were associated with an increased risk of vertigo. However, we did not find evidence for a causal effect of snoring, overall sleep duration, long sleep duration, short sleep duration, insomnia, and excessive daytime sleepiness on vertigo. No reverse causality was detected. CONCLUSION: Our findings suggest that abnormal sleep patterns may serve as risk factors for vertigo disorders and offer opportunities for the prevention and management of vertigo disorders.

Humans

Sleep disturbances in children and adolescents with iron deficiency: Questionnaire-based and actigraphic findings.

OBJECTIVE: Iron deficiency (ID), without or with anemia (IDA), has been linked to restless sleep and sleep-related movement disorders in childhood, but objective correlates are incompletely defined. We aimed to describe caregiver-reported sleep disturbances, restless legs syndrome (RLS) - related symptoms, and actigraphic sleep patterns in children and adolescents with ID/IDA, and to compare these findings with available sleep-asymptomatic control datasets. We finally explored short-term changes after iron supplementation. METHODS: In this single-center pilot observational study, 31 children with ID/IDA underwent baseline clinical/laboratory assessment and caregiver-reported sleep evaluation with the Sleep Disturbance Scale for Children (SDSC) plus RLS-oriented items. Sixteen also completed home actigraphy, and 8 had follow-up after iron treatment prescribed in routine care. Baseline findings were compared with historical healthy control datasets without reported sleep disturbances; iron-status data were not available for the questionnaire control group; within-subject changes were explored in the follow-up subgroup. RESULTS: Compared with healthy controls, the ID/IDA cohort had higher SDSC total scores (43.97&#x202f;&#xb1;&#x202f;9.63 vs 34.61&#x202f;&#xb1;&#x202f;7.50; p&#x202f;<&#x202f;0.001), with significant differences in the subscales difficulty in initiating and maintaining sleep (DIMS), sleep-wake transition disorders (SWTD), and sleep hyperhidrosis (SHY). Ten of 31 screened children (32.25%) had clinically plausible RLS-related symptoms and higher SWTD scores. Actigraphy showed shorter sleep duration, lower sleep efficiency, longer wake after sleep onset, and greater fragmentation. After iron treatment, parent reported restlessness improved, whereas actigraphic parameters showed only partial normalization. CONCLUSIONS: Pediatric ID/IDA was associated with caregiver-reported and actigraphic sleep disruption, characterized by restless and fragmented sleep. These findings support systematic sleep assessment in children with low iron stores and consideration of iron status in the work-up of restless or nonrestorative sleep.

Humans

[Sujective evaluation of the duration of sleep periods: role of actual time and the representation rate of different EEG stages].

Subjective estimations of the duration of night sleep periods and their actual duration were compared in 29 healthy men 21--36 years of age, awoken from the night sleep. The comparisons concerned the duration of consecutive sleep cycles, long (almost whole sleep cycles) and short ("parts of the cycles") periods, short periods ("parts of the cycle") without REM and with it. It has been found that long and short sleep periods are correspondingly reflected in the subjective estimation of their duration. The comparison of the estimation rates of various stages revealed that the highest subjective estimation, reduced to an hour of real time (subjective "hour estimation") in the first three sleep cycles characterises the cycle parts, including REM, whereas the lowest one--cycle parts, represented only by slow sleep stages, including delta-sleep. Subjective estimation of the sleep cycle duration regularly lowers throughout night sleep from evening till morning. Thus, subjective estimation of the duration of sleep periods is determined by two factors: their actual duration and manifestation rate of different sleep stages. The course of subjective time count in the sleep cycle seems to be uneven: it is slowed down in delta-sleep and accelerated in REM sleep following delta-sleep.

Adult

Preference studies of triazolam with standard hypnotics in out-patients with insomnia.

One hundred and four patients suffering from insomnia took part in four different two-night double-blind crossover trials of triazolam. In three separate studies, triazolam 0-5 mg was compared to placebo, flurazepam 30 mg and chloral hydrate 500 mg. Triazolam 0-5 mg was found to be preferred and to be superior to placebo, flurazepam and chloral hydrate in the treatment of insomnia. Analysis of sleep questionnaire data showed triazolam to be superior to the other treatments on the following: How much did the medication help you sleep, onset of sleep, duration of sleep and number of awakenings. Additionally, triazolam was superior to chloral hydrate on the feeling in the morning parameter. In another comparison of triazolam 0-25 mg to flurazepan 15 mg, triazolam was not significantly better than flurazepam on any of the efficacy parameters except that the patients felt more alert the morning following triazolam that following flurazepam. On all efficacy endpoints, trends for all parameters favoured triazolam 0-25 mg over flurazepam 15 mg. Untoward side-effects in these four studies were minimal.

Adolescent

A clinical comparison of triazolam with placebo and with secobarbital in insomniac patients.

Seventy-six out-patient insomniacs participated in three different two-night, double-blind crossover trials investigating the hypnotic efficacy andsafety of triazolam. Triazolam 0.5 mg was compared to placebo in one trial conducted K Kay Okawa, MD, and triazolam 0.5 mg was compared to secobarbital 100 mg in trials conducted by K Kay Okawa, MD and George S Allen, MD. The results of the later two studies were combined and the data analyzed jointly. Triazolam 0.5 mg was found to be preferred and to be significantly better than both placebo and secobarbital 100 mg in the treatment of insomnia. Analysis of sleep questionnaire data showed triazolam to be superior to either placebo or secobarbital on the following parameters: how much the medication helped the patients sleep; onset of sleep; duration of sleep; and number of nocturnal awakenings. No differences were observed between treatments in any trial with regard to the patient's feeling of alertness the next morning. The side-effects reported for all treatments did not significantly interfere with the patient's ability to function.

Adult

A systematic review of sleep hygiene interventions in physically and operationally demanding occupations.

Workers in physically and operationally demanding (POD) occupations (e.g. military personnel, emergency responders, law enforcement) experience disrupted sleep due to irregular schedules and high-stress work environments. Given the importance of sleep for physical and cognitive performance, interventions to improve sleep in POD occupations are crucial yet remain under-researched. To investigate the effectiveness of sleep hygiene interventions in improving sleep quality and quantity outcomes for POD occupations, a systematic review was conducted across five databases (PubMed, CINAHL, SPORTDiscus, PsycINFO, Web of Science) in September 2024. Eligible studies involved workers in POD occupations where a sleep hygiene intervention was compared against a waitlist or passive control. Ten studies were included, eight randomised controlled trials (RCTs) and two non-randomised controlled trials (NRCTs). Narrative synthesis identified Structured Training Programs (n&#x202f;=&#x202f;7), Phone Assistance Programs (n&#x202f;=&#x202f;2), and Single Lecture Interventions (n&#x202f;=&#x202f;1). Evidence certainty ranged from Very Low to Moderate, converging towards Low quality due to imprecision, risk of bias, and indirectness. Structured Training Programs showed moderate improvements in sleep quality and small-to-moderate effects on sleep duration. Phone Assistance Programs had minimal effects, and Single Lecture Interventions had negligible impact. Higher-quality research is urgently needed to assess sleep hygiene interventions in POD occupations.

Humans

Short and long sleep and sleeping pills. Is increased mortality associated?

Prospective epidemiologic data of the American Cancer Society disclosed that reported usual sleep durations among groups who complained of insomnia and sleeping pill use "often" overlapped with those of groups who had no complaints. Reports of insomnia were not consistently associated with increased mortality when several factors were controlled; however, men who reported usually sleeping less than four hours were 2.80 times as likely to have died within six years as men who reported 7.0 to 7.9 hours of sleep. The ratio for women was 1.48. Men and women who reported sleeping ten hours or more had about 1.8 times the mortality of those who reported 7.0 to 7.9 hours of sleep. Those who reported using sleeping pills "often" had 1.5 times the mortality of those who "never" used sleeping pills. These results do not prove that mortality could be reduced by altering sleep durations or by reducing hypnotic prescribing. Rather, studies are needed to determine the causes of these mortality risk factors.

Adult