Large-language models facilitate discovery of the molecular signatures regulating sleep and activity.

Sleep, locomotor and social activities are essential animal behaviors, but their reciprocal relationships and underlying mechanisms remain poorly understood. Here, we elicit information from a cutting-edge large-language model (LLM), generative pre-trained transformer (GPT) 3.5, which interprets 10.2-13.8% of Drosophila genes known to regulate the 3 behaviors. We develop an instrument for simultaneous video tracking of multiple moving objects, and conduct a genome-wide screen. We have identified 758 fly genes that regulate sleep and activities, including mre11 which regulates sleep only in the presence of conspecifics, and NELF-B which regulates sleep regardless of whether conspecifics are present. Based on LLM-reasoning, an educated signal web is modeled for understanding of potential relationships between its components, presenting comprehensive molecular signatures that control sleep, locomotor and social activities. This LLM-aided strategy may also be helpful for addressing other complex scientific questions.

Causality between sleep traits and the risk of frailty: a Mendelian randomization study.

Background: Research based on observation has demonstrated a relationship between sleep traits and frailty; however, it remains uncertain if this correlation indicates causation. The purpose of this study was to look at the causal relationship that exists between frailty and sleep traits. Method: Using summaries from a genome-wide association study of self-reported sleep features and frailty index, we performed a bidirectional Mendelian randomization (MR) analysis. Examining the causal relationships between seven sleep-related traits and frailty was the goal. The major method used to calculate effect estimates was the inverse-variance weighted method, supplemented by the weighted median and MR-Egger approaches. The study investigated pleiotropy and heterogeneity using several methodologies, such as the MR-Egger intercept, the MR-PRESSO approach, and the Cochran's Q test. We took multivariate Mendelian randomization and genetic correlations between related traits to enhance the confidence of the results. Furthermore, we used MRlap to correct for any estimation bias due to sample overlap. Results: Insomnia, napping during the day, and sleep apnea syndrome exhibited a positive connection with the frailty index in forward MR analysis. Conversely, there is a negative link between getting up in the morning, snoring and sleep duration with the frailty index. During the reverse MR analysis, the frailty index exhibited a positive correlation with insomnia, napping during the day, and sleep apnea syndrome, while demonstrating a negative correlation with sleep duration. There was no direct correlation between snoring, chronotype, and frailty. In MVMR analyses, the causal effect of sleep characteristics on frailty indices remained consistent after adjusting for potential confounders including BMI, smoking, and triglycerides. Conclusion: The findings of our investigation yield novel evidence that substantiates the notion of a bidirectional causal connection between sleep traits and frailty. Through the optimization of sleep, it is potentially feasible to hinder, postpone, or even reverse the state of frailty, and we proposed relevant interventions.

Association of genetically determined chronotype with circulating testosterone: a Mendelian randomization study.

Low testosterone levels in men have been linked to decreased physical and mental function, as well as a reduced quality of life. Previous prospective observational studies have suggested an association between testosterone and sleep traits, but the causality of this relationship remains unclear. We aimed to explore the potential causal link between genetically determined sleep traits and testosterone levels in men using Mendelian randomization (MR) analysis from the UK Biobank dataset. Our exposures were genetic variants associated with sleep traits (chronotype and sleep duration), whereas our outcomes were traits of sex steroid hormones (total testosterone, TT; bioavailable testosterone, BAT; and sex hormone-binding globulin, SHBG). We employed inverse variance weighted (IVW) and weighted median (WM) methods to assess the causal associations. The IVW method offers a robust estimate of causality, whereas the WM method provides reliable results even when some genetic variants are invalid instruments. Our main analysis involving sex steroid hormones and chronotype identified 155 chronotype-related variants. The primary findings from the analysis, which used chronotype as the exposure and sex steroid hormones as the outcomes, showed that a genetically predicted chronotype score was significantly associated with an increased levels of TT (association coefficient ß, 0.08; 95% confidence interval [CI], 0.02-0.14; P = 0.008) and BAT (ß, 0.08; 95% CI, 0.02-0.14; P = 0.007), whereas there was no significant association with SHBG (ß, 0.01; 95% CI, -0.02-0.03; P = 0.64). Meanwhile, MR analysis of sex steroid hormones and sleep duration was performed, and 69 variants associated with sleep duration were extracted. There were no significant association between sleep duration and sex steroid hormones (TT, P = 0.91; BAT, P = 0.82; and SHBG, P = 0.95). Our data support a causal association between chronotype and circulating testosterone levels in men. These findings underscore a potential causal relationship between chronotype and testosterone levels in men, suggesting that lifestyle adjustments are crucial for men's health. Recognizing factors that influence testosterone is essential. One limitation of this study is the use of one-sample MR, which can introduce potential bias due to non-independence of genetic associations for exposure and outcome. In conclusion, our findings indicate that a morning preference is correlated with circulating testosterone levels, emphasizing the potential impact of lifestyle habits on testosterone levels in men.

Variants in the circadian clock genes PER2 and PER3 associate with familial sleep phase disorders.

Delayed sleep phase disorder and advanced sleep phase disorder cause disruption of the circadian clock and present with extreme morning/evening chronotype with unclear role of the genetic etiology, especially for delayed sleep phase disorder. To assess if genotyping can aid in clinical diagnosis, we examined the presence of genetic variants in circadian clock genes previously linked to both sleep disorders in Slovenian patient cohort. Based on Morning-evening questionnaire, we found 15 patients with extreme chronotypes, 13 evening and 2 morning, and 28 controls. Sanger sequencing was used to determine the presence of carefully selected candidate SNPs in regions of the CSNK1D, PER2/3 and CRY1 genes. In a patient with an extreme morning chronotype and a family history of circadian sleep disorder we identified two heterozygous missense variants in PER3 gene, c.1243C>G (NM_001377275.1 (p.Pro415Ala)) and c.1250A>G (NM_001377275.1 (p.His417Arg)). The variants were significantly linked to Advanced sleep phase disorder and were also found in proband's father with extreme morningness. Additionally, a rare SNP was found in PER2 gene in a patient with clinical picture of Delayed sleep phase disorder. The novel variant in PER2 (NM_022817.3):c.1901-218 G>T was found in proband's parent with eveningness, indicating an autosomal dominant inheritance. We identified a family with autosomal dominant inheritance of two PER3 heterozygous variants that can be linked to Advanced sleep phase disorder. We revealed also a rare hereditary form of Delayed sleep phase disorder with a new PER2 variant with autosomal dominant inheritance, shedding the light into the genetic causality.

Lifestyle and genetic predisposition are associated with incident irritable bowel syndrome: A population-based prospective cohort study.

Few prospective studies have investigated the joint effect of lifestyle factors and genetic susceptibility on the risk of irritable bowel syndrome (IBS). This study aims to evaluate the associations of lifestyle and genetic factors with incident IBS in the UK Biobank. We analyzed data from 481,057 participants (54% female) without prevalent IBS at enrollment in the UK Biobank. An overall healthy lifestyle was defined using six modifiable lifestyle factors, including smoking, body mass index (BMI), sleep duration, diet, physical activity, and alcohol consumption, and hence categorized into 'favorable', 'intermediate', and 'unfavorable' lifestyles. A Cox proportional hazard model was used to investigate the association between a healthy lifestyle and incident IBS. Furthermore, we constructed a polygenic risk score (PRS) for IBS and assessed whether lifestyle modified the effect of genetics on the development of IBS. During a median follow-up of 12.1 years, 8645 incident IBS were ascertained. Specifically, among the six modifiable lifestyle factors, adequate sleep demonstrates the greatest protective effect (hazard ratio [HR]: 0.72, 95% CI: 0.69,0.75) against IBS. Compared with a favorable lifestyle, an unfavorable lifestyle was associated with a 56% (95% CI: 46%-67%) increased risk of IBS (P = 8.99 × 10-40). The risk of incident IBS was 12% (95% CI: 4%-21%) higher among those at high genetic risk compared with those at low genetic risk (P = 0.005). When considering the joint effect of lifestyle and genetic susceptibility, the HR nearly doubled among individuals with high genetic risk and unfavorable lifestyle (HR: 1.80; 95% CI:1.51-2.15; P = 3.50 × 10-11) compared to those with low genetic risk and favorable lifestyle. No multiplicative or addictive interaction was observed between lifestyle and genetics. The findings from this study indicated that lifestyle and genetic factors were independently associated with the risk of incident IBS. All these results implicated a possible clinical strategy of lowering the incidence of IBS by advocating a healthy lifestyle.

Single-nucleus RNA-seq identifies one galanin neuronal subtype in mouse preoptic hypothalamus activated during recovery from sleep deprivation.

The preoptic area of the hypothalamus (POA) is essential for sleep regulation. However, the cellular makeup of the POA is heterogeneous, and the molecular identities of the sleep-promoting cells remain elusive. To address this question, this study compares mice during recovery sleep following sleep deprivation to mice allowed extended sleep. Single-nucleus RNA sequencing (single-nucleus RNA-seq) identifies one galanin inhibitory neuronal subtype that shows upregulation of rapid and delayed activity-regulated genes during recovery sleep. This cell type expresses higher levels of growth hormone receptor and lower levels of estrogen receptor compared to other galanin subtypes. single-nucleus RNA-seq also reveals cell-type-specific upregulation of purinergic receptor (P2ry14) and serotonin receptor (Htr2a) during recovery sleep in this neuronal subtype, suggesting possible mechanisms for sleep regulation. Studies with RNAscope validate the single-nucleus RNA-seq findings. Thus, the combined use of single-nucleus RNA-seq and activity-regulated genes identifies a neuronal subtype functionally involved in sleep regulation.

The role of glial and neuronal Eph/ephrin signaling in Drosophila mushroom body development and sleep and circadian behavior.

The Eph receptor, a prototypically large receptor protein tyrosine kinase, interacts with ephrin ligands, forming a bidirectional signaling system that impacts diverse brain functions. Eph receptors and ephrins mediate forward and reverse signaling, affecting neurogenesis, axon guidance, and synaptic signaling. While mammalian studies have emphasized their roles in neurogenesis and synaptic plasticity, the Drosophila counterparts are less studied, especially in glial cells, despite structural similarities. Using RNAi to modulate Eph/ephrin expression in Drosophila neurons and glia, we studied their roles in brain development and sleep and circadian behavior. Knockdown of neuronal ephrin disrupted mushroom body development, while glial knockdown had minimal impact. Surprisingly, disrupting ephrin in neurons or glial cells altered sleep and circadian rhythms, indicating a direct involvement in these behaviors independent from developmental effects. Further analysis revealed distinct sleep phenotypes between neuronal and glial knockdowns, underscoring the intricate interplay within the neural circuits that govern behavior. Glia-specific knockdowns showed altered sleep patterns and reduced circadian rhythmicity, suggesting an intricate role of glia in sleep regulation. Our findings challenge simplistic models of Eph/ephrin signaling limited to neuron-glia communication and emphasize the complexity of the regulatory networks modulating behavior. Future investigations targeting specific glial subtypes will enhance our understanding of Eph/ephrin signaling's role in sleep regulation across species.

Maternal Childhood Adversity and Infant Epigenetic Aging: Moderation by Restless Sleep During Pregnancy.

Maternal exposure to childhood adversity is associated with detrimental health outcomes throughout the lifespan and may have implications for offspring. Evidence links maternal adverse childhood experiences (ACEs) to detrimental birth outcomes, yet the impact on the infant's epigenome is unclear. Moreover, maternal sleep habits during pregnancy may influence this association. Here, we explore whether restless sleep during pregnancy moderates the association between exposure to maternal childhood adversity and infant epigenetic age acceleration in 332 mother-infant dyads (56% female; 39% Black; 25% Hispanic). During the 2nd trimester, mothers self-reported childhood adversity and past-week restless sleep; DNA methylation from umbilical vein endothelial cells was used to estimate five epigenetic clocks. Multivariable linear regression was used to test study hypotheses. Despite no evidence of main effects, there was evidence of an interaction between maternal ACEs and restless sleep in predicting infant epigenetic age acceleration using the EPIC Gestational Age clock. Only infants whose mothers reported exposure to both ACEs and restless sleep demonstrated accelerated epigenetic aging. Results provide preliminary evidence that maternal childhood adversity and sleep may influence the infant epigenome.

No bidirectional relationship between sleep phenotypes and risk of proliferative diabetic retinopathy: a two-sample Mendelian randomization study.

This study aimed to investigate the probable existence of a causal relationship between sleep phenotypes and proliferative diabetic retinopathy (PDR). Single nucleotide polymorphisms associated with sleep phenotypes were selected as instrumental variables at the genome-wide significance threshold (P < 5 × 10-8). Inverse-variance weighted was applied as the primary Mendelian randomization (MR) analysis method, and MR Egger regression, weighted median, simple mode, and weighted mode methods were used as complementary analysis methods to estimate the causal association between sleep phenotypes and PDR. Results indicated that genetically predicted sleep phenotypes had no causal effects on PDR risk after Bonferroni correction (P = 0.05/10) [Chronotype: P = 0.143; Daytime napping: P = 0.691; Daytime sleepiness: P = 0.473; Insomnia: P = 0.181; Long sleep duration: P = 0.671; Morning person:P = 0.113; Short sleep duration: P = 0.517; Obstructive sleep apnea: P = 0.091; Sleep duration: P = 0.216; and snoring: P = 0.014]. Meanwhile, there are no reverse causality for genetically predicted PDR on sleep phenotypes [Chronotype: P = 0.100; Daytime napping: P = 0.146; Daytime sleepiness: P = 0.469; Insomnia: P = 0.571; Long sleep duration: P = 0.779; Morning person: P = 0.040; Short sleep duration: P = 0.875; Obstructive sleep apnea: P = 0.628; Sleep duration: P = 0.896; and snoring: P = 0.047]. This study's findings did not support the causal effect of between sleep phenotypes and PDR. Whereas, longitudinal studies can further verify results validation.

Association between sleep traits and sarcopenia-related traits: A two-sample bidirectional Mendelian randomization study.

AIM: Despite limited evidence regarding the impact of sleep quality on sarcopenia, it is widely recognized as being associated with various diseases. This study aimed to explore the causal relationship between sleep traits and sarcopenia-related traits. METHODS: This study utilized a two-sample bidirectional Mendelian randomization analysis. Genetic genome-wide summary data of sleep quality indicators, including chronotype, morning wake-up time, sleep duration, daytime napping, insomnia and daytime dozing, were used. Data on sarcopenia-related traits, such as appendicular lean mass, grip strength of both hands, walking pace and waist circumference, were collected from a large cohort study. The primary method used was the inverse-variance weighted analysis. RESULTS: A causal association was found between chronotype and appendicular lean mass (odds ratio [OR] 1.019, 95% confidence interval [CI] 1.016-1.211, P = 0.021). Napping during the day was connected with walking pace (OR 0.879, 95% CI 0.834-0.928, P = 2.289 × 10-6) and waist circumference (OR 1.234, 95% CI 1.081-1.408, P = 0.002). Insomnia was related to lower grip strength of the right hand (OR 0.844, 95% CI 0.747-0.954, P = 0.007), left hand (OR 0.836, 95% CI 0.742-0.943, P = 0.003), as well as walking pace (OR 0.871, 95% CI 0.798-0.951, P = 0.002). Furthermore, the reverse Mendelian randomization analysis showed associations between certain sarcopenia-related traits and poor sleep quality. CONCLUSIONS: Some sleep traits were associated with the occurrence of sarcopenia. These findings emphasized the significance of prioritizing sleep quality as a preventive measure against sarcopenia. Geriatr Gerontol Int 2024; 24: 537-545.

Mice harboring the T316N variant in the GABAAR γ2 subunit exhibit sleep-related hypermotor epilepsy phenotypes and hypersynchronization in the thalamocortical pathway.

OBJECTIVE: Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy syndrome characterized by seizures that predominantly occur during sleep. The pathogenesis of these seizures remains unclear. We previously detected rare variants in GABRG2, which encodes the γ2 subunit of γ-aminobutyric acid type A receptor (GABAAR), in patients with SHE and demonstrated that these variants impaired GABAAR function in vitro. However, the mechanisms by which GABRG2 variants contribute to seizure attacks during sleep remain unclear. METHODS: In this study, we designed a knock-in (KI) mouse expressing the mouse Gabrg2 T316N variant, corresponding to human GABRG2 T317N variant, using CRISPR/Cas9. Continuous video-electroencephalogram monitoring and in vivo multichannel electrophysiological recordings were performed to explore seizure susceptibility to pentylenetetrazol (PTZ), alterations in the sleep-wake cycle, spontaneous seizure patterns, and synchronized activity in the motor thalamic nuclei (MoTN) and secondary motor cortex (M2). Circadian variations in the expression of total, membrane-bound, and synaptic GABAAR subunits were also investigated. RESULTS: No obvious changes in gross morphology were detected in Gabrg2T316N/+ mice compared to their wild-type (Gabrg2+/+) littermates. Gabrg2T316N/+ mice share key phenotypes with patients, including sleep fragmentation and spontaneous seizures during sleep. Gabrg2T316N/+ mice showed increased susceptibility to PTZ-induced seizures and higher mortality after seizures. Synchronization of the local field potentials between the MoTN and M2 was abnormally enhanced in Gabrg2T316N/+ mice during light phase, when sleep dominates, accompanied by increased local activities in the MoTN and M2. Interestingly, in Gabrg2+/+ mice, GABAAR γ2 subunits showed a circadian increase on the neuronal membrane and synaptosomes in the transition from dark phase to light phase, which was absent in Gabrg2T316N/+ mice. CONCLUSION: We generated a new SHE mouse model and provided in vivo evidence that rare variants of GABRG2 contribute to seizure attacks during sleep in SHE.

Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice.

Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.

Gene‒environment interaction effect of hypothalamic‒pituitary‒adrenal axis gene polymorphisms and job stress on the risk of sleep disturbances.

Background: Studies have shown that chronic exposure to job stress may increase the risk of sleep disturbances and that hypothalamic‒pituitary‒adrenal (HPA) axis gene polymorphisms may play an important role in the psychopathologic mechanisms of sleep disturbances. However, the interactions among job stress, gene polymorphisms and sleep disturbances have not been examined from the perspective of the HPA axis. This study aimed to know whether job stress is a risk factor for sleep disturbances and to further explore the effect of the HPA axis gene × job stress interaction on sleep disturbances among railway workers. Methods: In this cross-sectional study, 671 participants (363 males and 308 females) from the China Railway Fuzhou Branch were included. Sleep disturbances were evaluated with the Pittsburgh Sleep Quality Index (PSQI), and job stress was measured with the Effort-Reward Imbalance scale (ERI). Generalized multivariate dimensionality reduction (GMDR) models were used to assess gene‒environment interactions. Results: We found a significant positive correlation between job stress and sleep disturbances (P < 0.01). The FKBP5 rs1360780-T and rs4713916-A alleles and the CRHR1 rs110402-G allele were associated with increased sleep disturbance risk, with adjusted ORs (95% CIs) of 1.75 [1.38-2.22], 1.68 [1.30-2.18] and 1.43 [1.09-1.87], respectively. However, the FKBP5 rs9470080-T allele was a protective factor against sleep disturbances, with an OR (95% CI) of 0.65 [0.51-0.83]. GMDR analysis indicated that under job stress, individuals with the FKBP5 rs1368780-CT, rs4713916-GG, and rs9470080-CT genotypes and the CRHR1 rs110402-AA genotype had the greatest risk of sleep disturbances. Conclusions: Individuals carrying risk alleles who experience job stress may be at increased risk of sleep disturbances. These findings may provide new insights into stress-related sleep disturbances in occupational populations.

No evidence linking sleep traits with white blood cell counts: Multivariable-adjusted and Mendelian randomization analyses.

BACKGROUND: Disturbances in habitual sleep have been associated with multiple age-associated diseases. However, the biological mechanisms underpinning these associations remain largely unclear. We assessed the possible involvement of the circulating immune system by determining the associations between sleep traits and white blood cell counts using multivariable-adjusted linear regression and Mendelian randomization. METHODS: Cross-sectional multivariable-adjusted linear regression analyses were done using participants within the normal range of total white blood cell counts (>4.5 × 109 and <11.0 × 109/µL) from UK Biobank. For the sleep traits, we examined (short and long) sleep duration, chronotype, insomnia symptoms and daytime dozing. Two-sample Mendelian randomization analyses were done using instruments for sleep traits derived from European-ancestry participants from UK Biobank (over 410,000 participants) and using SNP-outcome data derived from European-ancestry participants from the Blood Cell Consortium (N = 563,946) to which no data from UK Biobank contributed. RESULTS: Using data from 357,656 participants (mean [standard deviation] age: 56.5 [8.1] years, and 44.4% men), we did not find evidence that disturbances in any of the studied sleep traits were associated with differences in blood cell counts (total, lymphocytes, neutrophiles, eosinophiles and basophiles). Also, we did not find associations between disturbances in any of the studied sleep traits and white blood cell counts using Mendelian Randomization. CONCLUSION: Based on the results from two different methodologies, disturbances in habitual sleep are unlikely to cause changes in blood cell counts and thereby differences in blood cell counts are unlikely to be underlying the observed sleep-disease associations.

Using Polygenic Scores for Circadian Rhythms to Predict Wellbeing, Depressive Symptoms, Chronotype, and Health.

The association between circadian rhythms and diseases has been well established, while the association with mental health is less explored. Given the heritable nature of circadian rhythms, this study aimed to investigate the relationship between genes underlying circadian rhythms and mental health outcomes, as well as a possible gene-environment correlation for circadian rhythms. Polygenic scores (PGSs) represent the genetic predisposition to develop a certain trait or disease. In a sample from the Netherlands Twin Register (N = 14,021), PGSs were calculated for two circadian rhythm measures: morningness and relative amplitude (RA). The PGSs were used to predict mental health outcomes such as subjective happiness, quality of life, and depressive symptoms. In addition, we performed the same prediction analysis in a within-family design in a subset of dizygotic twins. The PGS for morningness significantly predicted morningness (R2 = 1.55%) and depressive symptoms (R2 = 0.22%). The PGS for RA significantly predicted general health (R2 = 0.12%) and depressive symptoms (R2 = 0.20%). Item analysis of the depressive symptoms showed that 4 out of 14 items were significantly associated with the PGSs. Overall, the results showed that people with a genetic predisposition of being a morning person or with a high RA are likely to have fewer depressive symptoms. The four associated depressive symptoms described symptoms related to decision-making, energy, and feeling worthless or inferior, rather than sleep. Based on our findings future research should include a substantial role for circadian rhythms in depression research and should further explore the gene-environment correlation in circadian rhythms.

Shared genetic architecture and causal relationship between sleep behaviors and lifespan.

Poor sleep health is associated with a wide array of increased risk for cardiovascular, metabolic and mental health problems as well as all-cause mortality in observational studies, suggesting potential links between sleep health and lifespan. However, it has yet to be determined whether sleep health is genetically or/and causally associated with lifespan. In this study, we firstly studied the genome-wide genetic association between four sleep behaviors (short sleep duration, long sleep duration, insomnia, and sleep chronotype) and lifespan using GWAS summary statistics, and both sleep duration time and insomnia were negatively correlated with lifespan. Then, two-sample Mendelian randomization (MR) and multivariable MR analyses were applied to explore the causal effects between sleep behaviors and lifespan. We found that genetically predicted short sleep duration was causally and negatively associated with lifespan in univariable and multivariable MR analyses, and this effect was partially mediated by coronary artery disease (CAD), type 2 diabetes (T2D) and depression. In contrast, we found that insomnia had no causal effects on lifespan. Our results further confirmed the negative effects of short sleep duration on lifespan and suggested that extension of sleep may benefit the physical health of individuals with sleep loss. Further attention should be given to such public health issues.

A patient-enriched MEIS1 coding variant causes a restless legs syndrome-like phenotype in mice.

Restless legs syndrome (RLS) is a neurological disorder characterized by uncomfortable or unpleasant sensations in the legs during rest periods. To relieve these sensations, patients move their legs, causing sleep disruption. While the pathogenesis of RLS has yet to be resolved, there is a strong genetic association with the MEIS1 gene. A missense variant in MEIS1 is enriched sevenfold in people with RLS compared to non-affected individuals. We generated a mouse line carrying this mutation (p.Arg272His/c.815G>A), referred to herein as Meis1R272H/R272H (Meis1 point mutation), to determine whether it would phenotypically resemble RLS. As women are more prone to RLS, driven partly by an increased risk of developing RLS during pregnancy, we focused on female homozygous mice. We evaluated RLS-related outcomes, particularly sensorimotor behavior and sleep, in young and aged mice. Compared to noncarrier littermates, homozygous mice displayed very few differences. Significant hyperactivity occurred before the lights-on (rest) period in aged female mice, reflecting the age-dependent incidence of RLS. Sensory experiments involving tactile feedback (rotarod, wheel running, and hotplate) were only marginally different. Overall, RLS-like phenomena were not recapitulated except for the increased wake activity prior to rest. This is likely due to the focus on young mice. Nevertheless, the Meis1R272H mouse line is a potentially useful RLS model, carrying a clinically relevant variant and showing an age-dependent phenotype.

Expanding the clinical and genetic landscape of (developmental) epileptic encephalopathy with spike-and-wave activation in sleep: results from studies of a Turkish cohort.

The terms developmental epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-and-wave activation in sleep (EE-SWAS) designate a spectrum of conditions that are typified by different combinations of motor, cognitive, language, and behavioral regression linked to robust spike-and-wave activity during sleep. In this study, we aimed at describing the clinical and molecular findings in "(developmental) epileptic encephalopathy with spike-and-wave activation in sleep" (D)EE-SWAS) patients as well as at contributing to the genetic etiologic spectrum of (D)EE-SWAS. Single nucleotide polymorphism (SNP) array and whole-exome sequencing (WES) techniques were used to determine the underlying genetic etiologies. Of the 24 patients included in the study, 8 (33%) were female and 16 (67%) were male. The median age at onset of the first seizure was 4 years and the median age at diagnosis of (D)EE-SWAS was 5 years. Of the 24 cases included in the study, 13 were compatible with the clinical diagnosis of DEE-SWAS and 11 were compatible with the clinical diagnosis of EE-SWAS. Abnormal perinatal history was present in four cases (17%), and two cases (8%) had a family history of epilepsy. Approximately two-thirds (63%) of all patients had abnormalities detected on brain computerized tomography/magnetic resonance (CT/MR) imaging. After SNP array and WES analysis, the genetic etiology was revealed in 7 out of 24 (29%) cases. Three of the variants detected were novel (SLC12A5, DLG4, SLC9A6). This study revealed for the first time that Smith-Magenis syndrome, SCN8A-related DEE type 13 and SLC12A5 gene variation are involved in the genetic etiology of (D)EE-SWAS. (D)EE-SWAS is a genetically diverse disorder with underlying copy number variations and single-gene abnormalities. In the current investigation, rare novel variations in genes known to be related to (D)EE-SWAS and not previously reported genes to be related to (D)EE-SWAS were discovered, adding to the molecular genetic spectrum. Molecular etiology enables the patient and family to receive thorough and accurate genetic counseling as well as a personalized medicine approach.

Relationship Between Sleep Duration and Cognitive Function in Older Adults: Analysis of NHANES and UK Biobank GWAS Data.

OBJECTIVES: To explore the relationship between sleep duration and cognitive functions in older adults using NHANES, a national US population study dataset, and to explore the causal association with Mendelian randomization (MR) using the UK Biobank. METHODS: First, an observational study was conducted with the NHANES database with participants ≥60 years. Sleep duration was measured with accelerometers for 7 consecutive days. Participants were divided into habitual short sleep (<7 h) and long sleep (>9 h) groups. Cognitive functions were measured with the CERAD Word Learning sub-set, Animal Fluency, and Digit Symbol Substitution test (DSST). Multivariate regression models were used to explore relationships between sleep duration and cognitive functions. Second, bidirectional MR was conducted with data for self-reported sleep duration, which came from a genome-wide association study (GWAS) comprising 446,118 adults from the UK Biobank, and general cognitive performance, which was obtained from a recent GWAS study (N = 257,841). Inverse-variance weighted (IVW) was used as the primary estimation of the outcome. RESULTS: In the observational study, 2687 participants were included. Sleep duration was associated with cognitive functions in a non-linear way. Habitual long sleep (>9°h) was associated with lower scores on DSST (OR = 0.01, p = .003) in the fully-adjusted model. The association between habitual short sleep and cognitive functions was insignificant. For the MR, genetically predicted lower general cognitive performance was causally associated with a higher prevalence of habitual short sleep (OR = 0.97, p = 5.1 × 10-7) and long sleep (OR = 0.97, p = 8.87 × 10-16). DISCUSSION: Short and long sleep duration might be both causally associated with worse outcomes of cognitive functions in older adults, highlighting the importance of maintaining sleep health.

Association of sleep traits with myopia in children and adolescents: A meta-analysis and Mendelian randomization study.

PURPOSE: The association between sleep and myopia in children and adolescents has been reported, yet it remains controversial and inconclusive. This study aimed to investigate the influence of different sleep traits on the risk of myopia using meta-analytical and Mendelian randomization (MR) techniques. METHODS: The literature search was performed in August 31, 2023 based on PubMed, Embase, Web of Science, and Cochrane library. The meta-analysis of observational studies reporting the relationship between sleep and myopia was conducted. MR analyses were carried out to assess the causal impact of genetic pre-disposition for sleep traits on myopia. RESULTS: The results of the meta-analysis indicated a significant association between the risk of myopia and both short sleep duration [odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.08-1.42, P = 0.003] and long sleep duration (OR = 0.75, 95% CI = 0.66-0.86, P < 0.001). MR analyses revealed no significant causal associations of genetically determined sleep traits with myopia, including chronotype, sleep duration, short sleep duration and long sleep duration (all P > 0.05). CONCLUSIONS: No evidence was found to support a causal relationship between sleep traits and myopia. While sleep may not independently predict the risk of myopia, the potential impact of sleep on the occurrence and development of myopia cannot be disregarded.