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Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10 ) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.

Sleep bruxism (SB) and obstructive sleep apnea (OSA) are co-occurring sleep conditions. The study aimed to evaluate the association of selected single-nucleotide polymorphisms (SNPs) occurring within the genes of the serotonin and dopamine pathways in SB and OSA and investigate the relationship between them. The study group included 100 Caucasian patients. SB and OSA were diagnosed in 74 and 28 patients, respectively. In addition, 125 unrelated Caucasian healthy blood donors served as randomly selected controls to enable comparison of polymorphisms. The following SNPs were analyzed: rs2770304 and rs6313 within the serotonin receptor encoding gene (HTR2A ), rs4680 polymorphism of the catechol-O-methyltransferase ( COMT ) gene, and rs686 within the dopamine receptor ( DRD1 ) encoding gene. The prevalence of the DRD1 rs686 G variant ( GG homozygosity) was found to be high in the study group compared to the control group. Bruxism episode index (BEI) was found to be significantly increased in the HTR2A rs6313 TT homozygotes compared to the heterozygous patients. Moreover, within a group of the HTR2A rs2770304 TT homozygous cases, a statistically significant correlation was observed between BEI and apnea–hypopnea index. These results indicate that DRD1 rs686 may potentially affect predisposition to SB, that HTR2A rs6313 SNP may be involved in SB pathogenesis, and that HTR2A rs2770304 polymorphism might contribute to the association between SB and OSA. This suggests a possible genetic contribution to the etiology of primary SB.

BackgroundThis phase II RCT was conducted to determine the feasibility and acceptability of brief behavioral therapy for cancer-related insomnia (BBT-CI) in breast cancer patients undergoing chemotherapy. We also assessed the preliminary effects of BBT-CI on insomnia and circadian rhythm in comparison to a Healthy Eating Education Learning control condition (HEAL).MethodsOf the 71 participants recruited, 34 were randomised to receive BBT-CI and 37 to receive HEAL. Oncology staff was trained to deliver the intervention in four community clinics affiliated with the NCI. Insomnia was assessed with the Insomnia Severity Index (ISI), and circadian rhythm was assessed using a wrist-worn actiwatch.ResultsCommunity staff interveners delivered 72% of the intervention components, with a recruitment rate of 77% and an adherence rate of 73%, meeting acceptability and feasibility benchmarks. Those randomised to BBT-CI improved their ISI scores by 6.3 points compared to a 2.5-point improvement in those randomised to HEAL (P = 0.041). Actigraphy data indicated that circadian functioning improved in the BBT-CI arm as compared to the HEAL arm at post-intervention (all P-values <0.05).ConclusionsBBT-CI is an acceptable and feasible intervention that can be delivered directly in the community oncology setting by trained staff. The BBT-CI arm experienced significant improvements in insomnia and circadian rhythm as compared to the control condition.

Although snoring is common in the general population, its aetiology has been largely understudied. Here we report a genetic study on snoring ( n  ~ 408,000; snorers ~ 152,000) using data from the UK Biobank. We identify 42 genome-wide significant loci, with an SNP-based heritability estimate of ~10% on the liability scale. Genetic correlations with body mass index, alcohol intake, smoking, schizophrenia, anorexia nervosa and neuroticism are observed. Gene-based associations identify 173 genes, including DLEU7 , MSRB3 and POC5 , highlighting genes expressed in the brain, cerebellum, lungs, blood and oesophagus. We use polygenic scores (PGS) to predict recent snoring and probable obstructive sleep apnoea (OSA) in an independent Australian sample ( n  ~ 8000). Mendelian randomization analyses suggest a potential causal relationship between high BMI and snoring. Altogether, our results uncover insights into the aetiology of snoring as a complex sleep-related trait and its role in health and disease beyond it being a cardinal symptom of OSA. Snoring is common in the population and tends to be more prevalent in older and/or male individuals. Here, the authors perform GWAS for habitual snoring, identify 41 genomic loci and explore potential causal relationships with anthropometric and cardiometabolic disease traits.

Progress has been made in the elucidation of sleep and wakefulness regulation at the neurocircuit level 1 , 2 . However, the intracellular signalling pathways that regulate sleep and the neuron groups in which these intracellular mechanisms work remain largely unknown. Here, using a forward genetics approach in mice, we identify histone deacetylase 4 (HDAC4) as a sleep-regulating molecule. Haploinsufficiency of Hdac4 , a substrate of salt-inducible kinase 3 (SIK3) 3 , increased sleep. By contrast, mice that lacked SIK3 or its upstream kinase LKB1 in neurons or with a Hdac4 S245A mutation that confers resistance to phosphorylation by SIK3 showed decreased sleep. These findings indicate that LKB1–SIK3–HDAC4 constitute a signalling cascade that regulates sleep and wakefulness. We also performed targeted manipulation of SIK3 and HDAC4 in specific neurons and brain regions. This showed that SIK3 signalling in excitatory neurons located in the cerebral cortex and the hypothalamus positively regulates EEG delta power during non-rapid eye movement sleep (NREMS) and NREMS amount, respectively. A subset of transcripts biased towards synaptic functions was commonly regulated in cortical glutamatergic neurons through the expression of a gain-of-function allele of Sik3 and through sleep deprivation. These findings suggest that NREMS quantity and depth are regulated by distinct groups of excitatory neurons through common intracellular signals. This study provides a basis for linking intracellular events and circuit-level mechanisms that control NREMS. Forward genetics analyses and targeted genetic manipulation in mice show that regulation of sleep quantity and quality is mediated by the LKB1–SIK3–HDAC4–HDAC5 pathway.

Multidimensional sleep trait, which is related to circadian rhythms closely, affects some cancers predominantly, while the relationship between sleep and lung cancer is rarely illustrated. We aimed to investigate whether sleep is causally associated with risk of lung cancer, through a two-sample Mendelian randomization study. The main analysis used publicly available GWAS summary data from two large consortia (UK Biobank and International Lung Cancer Consortium). Two-sample Mendelian randomization (MR) analysis was used to examine whether chronotype, getting up in the morning, sleep duration, nap during the day, or sleeplessness was causally associated with the risk of lung cancer. Additionally, multivariate MR analysis was also conducted to estimate the direct effects between sleep traits and lung cancer risks independent of smoking status including pack years of smoking or current tobacco smoking. There was no evidence of causal association between chronotype, getting up in the morning, or nap during the day and lung cancer. Sleeplessness was associated with higher risk of lung adenocarcinoma (odds ratio 5.75, 95% confidence intervals 2.12-15.65), while sleep duration played a protective role in lung cancer (0.46, 0.26-0.83). In multivariate MR analysis, sleeplessness and sleep duration remained to have similar results. In conclusion, we found robust evidence for effect of sleeplessness on lung adenocarcinoma risk and inconsistent evidence for a protective effect of sleep duration on lung cancer risk.

Sleep-wake disorders are highly prevalent disorders, which can lead to negative effects on cognitive, emotional and interpersonal functioning, and can cause maladaptive metabolic changes. Recent studies support the notion that metabolic processes correlate with sleep. The study of metabolite biomarkers (metabolomics) in a large-scale manner offers unique opportunities to provide insights into the pathology of diseases by revealing alterations in metabolic pathways. This review aims to summarize the status of metabolomic analyses-based knowledge on sleep disorders and to present knowledge in understanding the metabolic role of sleep in psychiatric disorders. Overall, findings suggest that sleep-wake disorders lead to pronounced alterations in specific metabolic pathways, which might contribute to the association of sleep disorders with other psychiatric disorders and medical conditions. These alterations are mainly related to changes in the metabolism of branched-chain amino acids, as well as glucose and lipid metabolism. In insomnia, alterations in branched-chain amino acid and glucose metabolism were shown among studies. In obstructive sleep apnea, biomarkers related to lipid metabolism seem to be of special importance. Future studies are needed to examine severity, subtypes and treatment of sleep-wake disorders in the context of metabolite levels.

Abstract Study Objectives Following sleep deprivation, increases in delta power have historically been used to index increases in sleep pressure. Research in mice has demonstrated that the homeostatic delta power response to sleep deprivation is heritable. Whether this is true in humans is unknown. In the present study, we used delta power and ORP, a novel measure of sleep depth, to investigate the effects of acute sleep deprivation on sleep depth and to assess the heritability of sleep homeostasis in humans. Methods ORP and delta power were examined during baseline and recovery sleep following 38 h of sleep deprivation in 57 monozygotic and 38 dizygotic same-sex twin pairs. Two complementary methods were used to estimate the trait heritability of sleep homeostasis. Results During recovery sleep, ORP was lower and delta power was higher than at baseline, indicating deeper sleep. However, at the end of the recovery night, delta power reached baseline levels but ORP demonstrated incomplete recovery. Both ORP and delta power showed a broad sense heritability of sleep homeostasis following sleep deprivation. The classical approach demonstrated an h2 estimate of 0.43 for ORP and 0.73 for delta power. Mixed-effect multilevel models showed that the proportion of variance attributable to additive genetic transmission was 0.499 (95% CI = 0.316–0.682; p < .0001) for ORP and 0.565 (95% CI = 0.403–0.726; p < .0001 for delta power. Conclusions These results demonstrate that the homeostatic response to sleep deprivation is a heritable trait in humans and confirm ORP as a robust measure of sleep depth. Graphical Abstract Graphical Abstract

Sleep is conserved from invertebrates to vertebrates, and is tightly regulated in a homeostatic manner. The molecular and cellular mechanisms that determine the amount of rapid eye movement sleep (REMS) and non-REMS (NREMS) remain unknown. Here we identify two dominant mutations that affect sleep and wakefulness by using an electroencephalogram/electromyogram-based screen of randomly mutagenized mice. A splicing mutation in the Sik3 protein kinase gene causes a profound decrease in total wake time, owing to an increase in inherent sleep need. Sleep deprivation affects phosphorylation of regulatory sites on the kinase, suggesting a role for SIK3 in the homeostatic regulation of sleep amount. Sik3 orthologues also regulate sleep in fruitflies and roundworms. A missense, gain-of-function mutation in the sodium leak channel NALCN reduces the total amount and episode duration of REMS, apparently by increasing the excitability of REMS-inhibiting neurons. Our results substantiate the use of a forward-genetics approach for studying sleep behaviours in mice, and demonstrate the role of SIK3 and NALCN in regulating the amount of NREMS and REMS, respectively. Two mutations affecting the sleep–wakefulness balance in mice are detected, showing that the SIK3 protein kinase is essential for determining daily wake time, and the NALCN cation channel regulates the duration of rapid eye movement sleep. Genes controlling sleep patterns Although the molecular pathways regulating circadian rhythms have been extensively explored and catalogued, much less is known about the molecular mechanisms controlling and driving sleep homeostasis. Using a forward genetic screen, Hiromasa Funato et al . identify two mutations affecting sleep/wakefulness balance. The Sik3 protein kinase was shown to be essential for determining total wake time, and mutations in the cation channel NALCN modulated REM sleep episode duration and total REM sleep time.

•First investigation of 5 G RF-EMF effects on NREM sleep spindles in genetic context.•Variant rs7304986 of CACNA1C modulates 5 G effects on spindle center frequency.•Exposure to 3.6 GHz 5 G RF-EMF accelerates spindle frequency in T/C allele carriers.•Spindle frequency in T/C carriers accelerated over widespread cortical areas.•Studies elucidating biological mechanisms underlying 5 G RF-EMF effects warranted. The introduction of 5G technology as the latest standard in mobile telecommunications has raised concerns about its potential health effects. Prior studies of earlier generations of radiofrequency electromagnetic fields (RF-EMF) demonstrated narrowband spectral increases in the electroencephalographic (EEG) spindle frequency range (11–16 Hz) in non-rapid-eye-movement (NREM) sleep. However, the impact of 5G RF-EMF on sleep remains unexplored. Additionally, RF-EMF can activate l-type voltage-gated calcium channels (LTCC), which have been linked to sleep quality and EEG oscillatory activity. This study investigates whether the allelic variant rs7304986 in the CACNA1C gene, encoding the α1C subunit of LTCC, modulates 5G RF-EMF effects on EEG spindle activity in NREM sleep. Thirty-four participants, genotyped for rs7304986 (15 T/C and 19 matched T/T carriers), underwent a double-blind, sham-controlled study with standardized left-hemisphere exposure to two 5G RF-EMF signals (3.6 GHz and 700 MHz) for 30 min before sleep. Sleep spindle activity was analyzed using high-density EEG and the Fitting Oscillations & One Over f (FOOOF) algorithm. T/C carriers reported longer sleep latency compared to T/T carriers. A significant interaction between RF-EMF exposure and rs7304986 genotype was observed, with only 3.6 GHz exposure in T/C carriers inducing a faster spindle center frequency in the central, parietal, and occipital cortex compared to sham. These findings suggest that 3.6 GHz 5G RF-EMF modulates spindle center frequency in NREM sleep in a CACNA1C genotype-dependent manner, implicating LTCC in the physiological response to RF-EMF and underscoring the need for further research into 5G effects on brain health.