ABSTRACT
RATIONALE: Comorbid insomnia and sleep apnea is reported to have worse outcomes than either condition alone. The local genetic correlations of these disorders are unknown. OBJECTIVES: To identify local genomic regions with heritability for clinically diagnosed sleep apnea and insomnia, and to identify local genetic correlations between these disorders and/or hypersomnia. METHODS: Fifty thousand two hundred seventeen patients of European ancestry were examined. Global and local heritability and genetic correlations for independent regions were calculated, adjusting for obesity and other covariates. RESULTS: Sleep apnea and insomnia were significantly globally heritable and had 118 and 168 genetic regions with local heritability p-values <.05, respectively. One region had a significant genetic correlation for sleep apnea and hypersomnia (p-value = 9.85 × 10-4). CONCLUSIONS: Clinically diagnosed sleep apnea and insomnia have minimal shared genetic architecture, supporting genetically distinct comorbid insomnia and sleep apnea components. However, additional correlated regions may be identified with additional sample size and methodological improvements.
Subject(s)
Disorders of Excessive Somnolence , Sleep Apnea Syndromes , Sleep Apnea, Obstructive , Sleep Initiation and Maintenance Disorders , Humans , Sleep Initiation and Maintenance Disorders/epidemiology , Sleep Initiation and Maintenance Disorders/genetics , Biological Specimen Banks , Sleep Apnea Syndromes/epidemiology , Sleep Apnea Syndromes/genetics , Disorders of Excessive Somnolence/epidemiology , Disorders of Excessive Somnolence/geneticsABSTRACT
BACKGROUND: Excessive daytime sleepiness (EDS), experienced in 10% to 20% of the population, has been associated with cardiovascular disease and death. However, the condition is heterogeneous and is prevalent in individuals having short and long sleep duration. We sought to clarify the relationship between sleep duration subtypes of EDS with cardiovascular outcomes, accounting for these subtypes. METHODS AND RESULTS: We defined 3 sleep duration subtypes of excessive daytime sleepiness: normal (6-9 hours), short (<6 hours), and long (>9 hours), and compared these with a nonsleepy, normal-sleep-duration reference group. We analyzed their associations with incident myocardial infarction (MI) and stroke using medical records of 355 901 UK Biobank participants and performed 2-sample Mendelian randomization for each outcome. Compared with healthy sleep, long-sleep EDS was associated with an 83% increased rate of MI (hazard ratio, 1.83 [95% CI, 1.21-2.77]) during 8.2-year median follow-up, adjusting for multiple health and sociodemographic factors. Mendelian randomization analysis provided supporting evidence of a causal role for a genetic long-sleep EDS subtype in MI (inverse-variance weighted ß=1.995, P=0.001). In contrast, we did not find evidence that other subtypes of EDS were associated with incident MI or any associations with stroke (P>0.05). CONCLUSIONS: Our study suggests the previous evidence linking EDS with increased cardiovascular disease risk may be primarily driven by the effect of its long-sleep subtype on higher risk of MI. Underlying mechanisms remain to be investigated but may involve sleep irregularity and circadian disruption, suggesting a need for novel interventions in this population.
Subject(s)
Cardiovascular Diseases , Disorders of Excessive Somnolence , Myocardial Infarction , Stroke , Humans , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/genetics , Disorders of Excessive Somnolence/diagnosis , Disorders of Excessive Somnolence/epidemiology , Disorders of Excessive Somnolence/genetics , Sleep , Myocardial Infarction/epidemiology , Myocardial Infarction/genetics , Myocardial Infarction/complications , Stroke/diagnosis , Stroke/epidemiology , Stroke/geneticsABSTRACT
Herein we focus on connections between genetics and some central disorders of hypersomnolence - narcolepsy types 1 and 2 (NT1, NT2), idiopathic hypersomnia (IH), and Kleine-Levin syndrome (KLS) - for a better understanding of their etiopathogenetic mechanisms and a better diagnostic and therapeutic definition. Gene pleiotropism influences neurological and sleep disorders such as hypersomnia; therefore, genetics allows us to uncover common pathways to different pathologies, with potential new therapeutic perspectives. An important body of evidence has accumulated on NT1 and IH, allowing a better understanding of etiopathogenesis, disease biomarkers, and possible new therapeutic approaches. Further studies are needed in the field of epigenetics, which has a potential role in the modulation of biological specific hypersomnia pathways.
Subject(s)
Disorders of Excessive Somnolence , Idiopathic Hypersomnia , Narcolepsy , Humans , Disorders of Excessive Somnolence/genetics , Disorders of Excessive Somnolence/diagnosis , Narcolepsy/genetics , Narcolepsy/diagnosis , Narcolepsy/drug therapy , Idiopathic Hypersomnia/diagnosis , Idiopathic Hypersomnia/drug therapy , Idiopathic Hypersomnia/genetics , Epigenesis, Genetic/geneticsABSTRACT
BACKGROUND: Some studies show an association between the apolipoprotein E ε4 allele (ApoEε4) and obstructive sleep apnea syndrome (OSAS), and other studies, an association between ApoEε4 and excessive daytime sleepiness (EDS), but there are no data in the literature on the interaction between EDS, cognitive function, and ApoEε4 in patients with OSA. OBJECTIVE: To examine the cognitive function of adults with and without EDS and with and without ApoEε4. METHODS: A total of 21 male and female patients aged between 33 and 79 years, underwent a clinical interview, ApoE genotyping, neuropsychological evaluation, polysomnography, and the application of the Epworth Sleepiness Scale. RESULTS: Excessive daytime sleepiness was associated with lower intelligence quotient (IQ; total performance) and worse immediate visual memory, regardless of the ApoE genotype. Patients carrying the ApoEε3/ε4 genotype had a worse performance in divided attention, constructional praxis, perceptual organization, and cognitive flexibility. A combination of the ε4 allele and EDS potentiates the negative effect on cognition, except for immediate visual memory. In this case, patients had a worse performance in terms of processing speed, selective attention, and visuomotor coordination. CONCLUSIONS: Excessive daytime sleepiness and the ApoEε3/ε4 genotype are associated with worse cognitive performance in OSA patients. The combination of EDS and ε4 allele potentiates cognitive impairment.
ANTECEDENTES: Alguns estudos mostram uma associação entre o alelo ε4 da apolipoproteina E (ApoEε4) e a síndrome da apneia obstrutiva do sono (SAOS), e outros, entre ApoEε4 e a sonolência excessiva diurna (SED), mas não há dados na literatura sobre a interação entre SED, função cognitiva e ApoEε4 em pacientes com SAOS. OBJETIVO: Avaliar a função cognitiva em adultos com SAOS com e sem SED e com e sem ApoEε4. MéTODOS: Ao todo, 21 pacientes, de 33 a 79 anos, homens e mulheres, foram avaliados clinicamente, e submetidos a genotipagem ApoE, avaliação neuropsicológica, polissonografia, e aplicação da Escala de Sonolência de Epworth. RESULTADOS: A SED esteve associada com menor quociente de inteligência (QI; desempenho geral) e pior memória visual imediata, independentemente do genótipo ApoE. Pacientes com genótipo ApoEε3/ε4 apresentaram pior desempenho na atenção dividida, praxe construcional, organização perceptiva e flexibilidade cognitiva. A combinação do alelo ε4 com a SED potencializa esse efeito deletério na cognição, exceto na memória visual imediata. Nesse caso, os pacientes tiveram uma menor velocidade de processamento cognitivo, e piores atenção seletiva e coordenação visiomotora. CONCLUSõES: A SED e o genótipo ApoEε3/ε4 estão associados a um pior desempenho cognitivo em pacientes com SAOS. A combinação de SED e do alelo ε4 potencializa esse efeito.
Subject(s)
Apolipoproteins E , Cognition , Disorders of Excessive Somnolence , Sleep Apnea, Obstructive , Adult , Aged , Female , Humans , Male , Middle Aged , Apolipoproteins E/genetics , Disorders of Excessive Somnolence/genetics , Disorders of Excessive Somnolence/complications , Genotype , Sleep Apnea, Obstructive/complicationsABSTRACT
STUDY OBJECTIVES: Narcolepsy type 1 (NT1) is associated with metabolic abnormalities but their etiology remains largely unknown. The gene for carnitine palmitoyltransferase 1B (CPT1B) and abnormally low serum acylcarnitine levels have been linked to NT1. To elucidate the details of altered fatty acid metabolism, we determined levels of individual acylcarnitines and evaluated CPT1 activity in patients with NT1 and other hypersomnia. METHODS: Blood samples from 57 NT1, 51 other hypersomnia patients, and 61 healthy controls were analyzed. The levels of 25 major individual acylcarnitines were determined and the C0/(t[C16] + t[C18]) ratio was used as a CPT1 activity marker. We further performed transcriptome analysis using independent blood samples from 42 NT1 and 42 healthy controls to study the relevance of fatty acid metabolism. NT1-specific changes in CPT1 activity and in expression of related genes were investigated. RESULTS: CPT1 activity was lower in patients with NT1 (p = 0.00064) and other hypersomnia (p = 0.0014) than in controls. Regression analysis revealed that CPT1 activity was an independent risk factor for NT1 (OR: 1.68; p = 0.0031) and for other hypersomnia (OR: 1.64; p = 0.0042). There was a significant interaction between obesity (BMI <25, ≥25) and the SNP rs5770917 status such that nonobese NT1 patients without risk allele had better CPT1 activity (p = 0.0089). The expression levels of carnitine-acylcarnitine translocase (CACT) and CPT2 in carnitine shuttle were lower in NT1 (p = 0.000051 and p = 0.00014, respectively). CONCLUSIONS: These results provide evidences that abnormal fatty acid metabolism is involved in the pathophysiology of NT1 and other hypersomnia.
Subject(s)
Carnitine O-Palmitoyltransferase , Disorders of Excessive Somnolence , Narcolepsy , Carnitine/analogs & derivatives , Carnitine/metabolism , Carnitine Acyltransferases/metabolism , Carnitine O-Palmitoyltransferase/genetics , Carnitine O-Palmitoyltransferase/metabolism , Disorders of Excessive Somnolence/complications , Disorders of Excessive Somnolence/genetics , Fatty Acids , Humans , Narcolepsy/genetics , Risk FactorsABSTRACT
INTRODUCTION: Kleine-Levin syndrome (KLS) is a rare and debilitating disorder presenting with periodic hypersomnolence, cognitive, psychiatric and behavioral disturbances. In the absence of biomarkers it can be difficult to diagnose. Rare LMOD3 variants in a family and in seven sporadic cases with KLS have been described. Here we report a patient and her family with an unclassified, familial, periodic central disorder of hypersomnolence (CDH) in whom the presence of a LMOD3 gene variant was assessed. CASE DESCRIPTION: The female patient presented since early adulthood with recurrent episodes of hypersomnolence. Over more than 20 years of follow-up the diagnoses of idiopathic hypersomnia, KLS and hypersomnia associated with a psychiatric condition were made. The family history is positive for periodic hypersomnolence and psychiatric conditions. The patient, her symptomatic mother and her asymptomatic sister carried a Proline for Histidine substitution at codon 552 of the LMOD3-gene. This variant was previously reported in two sporadic KLS patients and its frequency in the general population is below 0.02%. DISCUSSION: We report the association of periodic hypersomnia with a polymorphism of the LMOD3-gene in a patient with atypical KLS and a positive family history. Further research is needed to assess the pathological and predictive value of LMOD3 variants in KLS.
Subject(s)
Disorders of Excessive Somnolence , Idiopathic Hypersomnia , Kleine-Levin Syndrome , Adult , Disorders of Excessive Somnolence/complications , Disorders of Excessive Somnolence/diagnosis , Disorders of Excessive Somnolence/genetics , Female , Humans , Polymorphism, GeneticABSTRACT
Excessive daytime sleepiness is characterized by a persistent feeling of having trouble staying awake, typically with inappropriate sleep episodes. Orexin (hypocretin) is a neuropeptide that regulates sleep-wake cycles and rapid eye movement sleep. Several large-scale genome-wide association studies (GWASs) in European populations have found genetic variants in orexin receptor-1 (OX1R) and -2 (OX2R) that are associated with sleep traits including daytime sleepiness. To identify genetic variants associated with daytime sleepiness, we performed an association study of genetic variants in prepro-orexin, OX1R, and OX2R in 14,329 Japanese individuals from the Tohoku Medical Megabank Project cohort. A genetic variant in OX2R was significantly associated with self-reported daytime sleepiness after Bonferroni correction (rs188018846: P = 8.4E-05). In addition, a missense variant in OX2R identified by the European GWASs showed a nominally significant association with daytime sleepiness in a Japanese population (p.Ile308Val, rs2653349: P = 0.044). Multiple genetic variants in OX2R can affect daytime sleepiness in general populations.
Subject(s)
Disorders of Excessive Somnolence , Genome-Wide Association Study , Orexin Receptors/metabolism , Disorders of Excessive Somnolence/epidemiology , Disorders of Excessive Somnolence/genetics , Humans , Japan/epidemiology , Orexin Receptors/genetics , Orexins/genetics , Self ReportABSTRACT
OBJECTIVE: To determine whether narcolepsy Human Leukocyte Antigen (HLA) risk allele DQB1*0602 is associated with excessive daytime sleepiness (EDS) and inappropriate sleep in patients with Parkinson disease (PD). BACKGROUND: EDS is a common and disabling non-motor manifestation of PD, affecting quality of life and driving performance. DQB1*0602 is an HLA risk allele for narcolepsy. It is present in 12-30% of the general population. We hypothesize that DQB1*0602 is associated with an increased risk of EDS and inappropriate sleep in PD patients. METHODS: This was a cross-sectional observational study of 150 PD individuals on dopaminergic agents. Main outcome measures were DQB1*0602 status and the modified Epworth Sleepiness Scale. Individuals with dementia, loss of independence, narcolepsy and untreated sleep apnea were excluded. Confounding variables for EDS were assessed using Parkinson Disease Sleep Scale, Mayo Sleep Questionnaire, Unified PD Rating Scale, Hoehn and Yahr scale. RESULTS: DQB1*06:02 positive PD patients were approximately three times more likely to experience EDS and fall asleep inappropriately during activities that required sustained alertness (e.g. driving, eating, attending work etc.). Exploratory post hoc analysis showed a dopaminergic drug dose- and type- dependent effect on daytime sleepiness in DQB1*06:02 positive individuals. No significant differences were found in confounding variables. CONCLUSION: PD individuals are more likely to experience EDS and fall asleep inappropriately during activities if DQB1*0602 positive. Genetic vulnerability may explain EDS risk in PD.
Subject(s)
Disorders of Excessive Somnolence , Narcolepsy , Parkinson Disease , Cross-Sectional Studies , Disorders of Excessive Somnolence/genetics , Dopamine Agents , Genetic Markers , HLA-DQ beta-Chains , Humans , Narcolepsy/complications , Narcolepsy/drug therapy , Narcolepsy/genetics , Parkinson Disease/complications , Parkinson Disease/drug therapy , Parkinson Disease/genetics , Quality of LifeABSTRACT
The aim of this study is to determine the roles of global histone acetylation (Ac)/methylation (me), their modifying enzymes, and gene-specific histone enrichment in obstructive sleep apnea (OSA). Global histone modifications, and their modifying enzyme expressions were assessed in peripheral blood mononuclear cells from 56 patients with OSA and 16 matched subjects with primary snoring (PS). HIF-1α gene promoter-specific H3K36Ac enrichment was assessed in another cohort (28 OSA, 8 PS). Both global histone H3K23Ac and H3K36Ac expressions were decreased in OSA patients versus PS subjects. H3K23Ac expressions were further decreased in OSA patients with prevalent hypertension. HDAC1 expressions were higher in OSA patients, especially in those with excessive daytime sleepiness, and reduced after more than 6 months of continuous positive airway pressure treatment. H3K79me3 expression was increased in those with high C-reactive protein levels. Decreased KDM6B protein expressions were noted in those with a high hypoxic load, and associated with a higher risk for incident cardiovascular events or hypertension. HIF-1α gene promoter-specific H3K36Ac enrichment was decreased in OSA patients versus PS subjects. In vitro intermittent hypoxia with re-oxygenation stimuli resulted in HDAC1 over-expression and HIF-1α gene promoter-specific H3K36Ac under-expression, while HDAC1 inhibitor, SAHA, reversed oxidative stress through inhibiting NOX1. In conclusions, H3K23/H3K36 hypoacetylation is associated with the development of hypertension and disease severity in sleep-disordered breathing patients, probably through up-regulation of HDAC1, while H3K79 hypermethylation is associated with higher risk of cardiovascular diseases, probably through down-regulation of KDM6B.
Subject(s)
Histone Deacetylase 1/genetics , Histones/genetics , Sleep Apnea, Obstructive/genetics , Up-Regulation/genetics , Acetylation , Adult , C-Reactive Protein/genetics , Case-Control Studies , Cohort Studies , Continuous Positive Airway Pressure/methods , DNA Methylation/genetics , Disorders of Excessive Somnolence/genetics , Female , Humans , Hypoxia/genetics , Jumonji Domain-Containing Histone Demethylases/genetics , Leukocytes, Mononuclear/physiology , Male , Middle Aged , NADPH Oxidase 1/genetics , Polysomnography/methods , Promoter Regions, Genetic/genetics , Sleep Apnea Syndromes/genetics , Snoring/genetics , THP-1 CellsABSTRACT
OBJECTIVE: Daytime sleepiness is known to be related to stroke, but whether daytime sleepiness is a risk factor for stroke remains unclear. We conducted a two-sample Mendelian randomization study to assess the relationship between daytime sleepiness and stroke, ischemic stroke (IS) and IS subtypes. METHODS: Thirty-six single-nucleotide polymorphisms (SNPs) associated with daytime sleepiness were selected as instrumental variables, which were identified from a recent genome-wide association study(N = 452,071). Summary statistics of the SNPs on stroke, IS and IS subtypes were derived from the MEGASTROKE consortium with 40,585 stroke cases and 406,111 controls. RESULTS: We found that daytime sleepiness was associated with large artery stroke (OR, 6.75; 95%CI, 1.49-30.57; p = 0.013), but not with all stroke (OR, 1.29; 95%CI, 0.81-2.05; p = 0.282), all ischemic stroke(OR, 1.46; 95%CI, 0.90-2.39; p = 0.136), cardioembolic stroke(OR, 1.0; 95%CI, 0.39-2.64; p = 0.984), or small artery stroke(OR, 1.52; 95%CI, 0.46-5.05; p = 0.485). CONCLUSION: Our findings indicated that daytime sleepiness is causally associated with an increased risk of large artery stroke. Further studies are necessary to verify our results and explain the physiological mechanisms.
Subject(s)
Disorders of Excessive Somnolence/complications , Polymorphism, Single Nucleotide , Stroke/etiology , Case-Control Studies , Disorders of Excessive Somnolence/genetics , Genome-Wide Association Study , Humans , Mendelian Randomization Analysis , Risk Factors , Stroke/geneticsABSTRACT
STUDY OBJECTIVES: Patients with unexplained hypersomnolence have significant impairment related to daytime sleepiness and excessive sleep duration, the biological bases of which are poorly understood. This investigation sought to examine relationships between objectively measured hypersomnolence phenotypes and epigenetic modification of candidate hypersomnolence genes to advance this line of inquiry. METHODS: Twenty-eight unmedicated clinical patients with unexplained hypersomnolence were evaluated using overnight ad libitum polysomnography, multiple sleep latency testing, infrared pupillometry, and the psychomotor vigilance task. DNA methylation levels on CpG sites annotated to 11 a priori hypersomnolence candidate genes were assessed for statistical association with hypersomnolence measures using independent regression models with adjusted local index of significance (aLIS) P-value threshold of 0.05. RESULTS: Nine CpG sites exhibited significant associations between DNA methylation levels and total sleep time measured using ad libitum polysomnography (aLIS p-value < .05). All nine differentially methylated CpG sites were annotated to the paired box 8 (PAX8) gene and its related antisense gene (PAX8-AS1). Among these nine differentially methylated positions was a cluster of five CpG sites located in the body of the PAX8 gene and promoter of PAX8-AS1. CONCLUSIONS: This study demonstrates that PAX8/PAX8-AS1 DNA methylation levels are associated with total sleep time in persons with unexplained hypersomnolence. Given prior investigations that have implicated single nucleotide polymorphisms in PAX8/PAX8-AS1 with habitual sleep duration, further research that clarifies the role of DNA methylation levels on these genes in the phenotypic expression of total sleep time is warranted.
Subject(s)
DNA Methylation , Disorders of Excessive Somnolence/genetics , PAX8 Transcription Factor/genetics , RNA, Long Noncoding/genetics , Humans , Polysomnography , Sleep Latency , WakefulnessABSTRACT
BACKGROUND: Parthenogenetic mosaicism is an extremely rare condition identified only in five subjects to date. The previous studies indicate that this condition is mediated by parthenogenetic activation and is free from a specific phenotype ascribed to unmaking of a maternally inherited recessive variant in the parthenogenetic cell lineage. RESULTS: We examined a 28-year-old Japanese 46,XX female with Silver-Russell syndrome and idiopathic hypersomnia. The results revealed (1) predominance of maternally derived alleles for all the differentially methylated regions examined; (2) no disease-related copy-number variant; (3) two types of regions for all chromosomes, i.e., four BAF (B-allele frequency) band regions with single major microsatellite peaks of maternal origin and single minor microsatellite peaks of non-maternal (paternal) origin, and six BAF band regions with single major microsatellite peaks of maternal origin and two minor microsatellite peaks of maternal and non-maternal (paternal) origin; (4) an unmasked extremely rare PER2 variant (c.1403G>A:p.(Arg468Gln)) with high predicted pathogenicity; (5) mildly affected local structure with altered hydrogen bonds of the p.Arg468Gln-PER2 protein; and (6) nucleus-dominant subcellular distribution of the p.Arg468Gln-PER2 protein. CONCLUSIONS: The above findings imply that the second polar body retention occurred around fertilization, resulting in the generation of the parthenogenetic cell lineage by endoreplication of a female pronucleus and the normal cell lineage by fusion of male and female pronuclei, and that the homozygous PER2 variant in the parthenogenetic cells is the likely causative factor for idiopathic hypersomnia.
Subject(s)
Asian People/genetics , Disorders of Excessive Somnolence/genetics , Genetic Predisposition to Disease , Mosaicism , Parthenogenesis/genetics , Period Circadian Proteins/genetics , Polar Bodies , Adult , Disorders of Excessive Somnolence/physiopathology , Female , Genetic Variation , Genotype , HumansABSTRACT
Michel Jouvet proposed in 1959 that REM sleep is a paradoxical state since it was characterized by the association of a cortical activation similar to wakefulness (W) with muscle atonia. Recently, we showed using cFos as a marker of activity that cortical activation during paradoxical sleep (PS) was limited to a few limbic cortical structures in contrast to W during which all cortices were strongly activated. However, we were not able to demonstrate whether the same neurons are activated during PS and W and to rule out that the activation observed was not linked with stress induced by the flowerpot method of PS deprivation. In the present study, we answered to these two questions by combining tdTomato and cFos immunostaining in the innovative TRAP2 transgenic mice exposed one week apart to two periods of W (W-W mice), PS rebound (PSR-PSR) or a period of W followed by a period of PSR (W-PSR mice). Using such method, we showed that different neurons are activated during W and PSR in the anterior cingulate (ACA) and rostral and caudal retrosplenial (rRSP and cRSP) cortices as well as the claustrum (CLA) previously shown to contain a large number of activated neurons after PSR. Further, the distribution of the neurons during PSR in the rRSP and cRSP was limited to the superficial layers while it was widespread across all layers during W. Our results clearly show at the cellular level that PS and W are two completely different states in term of neocortical activation.
Subject(s)
Claustrum/physiology , Disorders of Excessive Somnolence/physiopathology , Gyrus Cinguli/physiology , Neurons/physiology , Sleep, REM/physiology , Wakefulness/physiology , Animals , Claustrum/cytology , Disorders of Excessive Somnolence/genetics , Disorders of Excessive Somnolence/pathology , Female , Gyrus Cinguli/cytology , Male , Mice , Mice, Transgenic , Polysomnography/methodsABSTRACT
PURPOSE OF REVIEW: This article discusses the central disorders of hypersomnolence, a group of disorders resulting in pathologic daytime sleepiness, particularly narcolepsy type 1 and narcolepsy type 2, idiopathic hypersomnia, and Kleine-Levin syndrome. Disease features, diagnostic testing, epidemiology, pathophysiology, and treatment are reviewed. RECENT FINDINGS: Increasing evidence implicates autoimmunity in narcolepsy type 1, including a strong association with human leukocyte antigen-DQB1*06:02, association with a polymorphism in the T-cell receptor alpha locus in genome-wide association, and the identification of autoreactive T cells in patients with this type of narcolepsy. In contrast, the cause or causes of narcolepsy type 2 and idiopathic hypersomnia are unknown. Multiple treatment options exist, including two medications approved for the treatment of narcolepsy by the US Food and Drug Administration (FDA) in 2019. These include solriamfetol, a dopamine- and norepinephrine-reuptake inhibitor, and pitolisant, an H3-inverse agonist/antagonist that increases histaminergic neurotransmission. SUMMARY: The central disorders of hypersomnolence all cause severe sleepiness but can be differentiated based on ancillary symptoms, diagnostic testing, and pathophysiology. It is important that these disorders are identified because multiple treatments are available to improve functioning and quality of life.
Subject(s)
Disorders of Excessive Somnolence/drug therapy , Disorders of Excessive Somnolence/genetics , Disorders of Excessive Somnolence/immunology , HumansABSTRACT
The cFos immunostaining allowed the identification of multiple populations of neurons involved in the generation of paradoxical sleep. We adopted the transgenic (targeted recombination in active populations) mouse model, which following injection of tamoxifen, allows expression of Cre-dependent reporter constructs (i.e., mCherry) in neurons expressing cFos during waking or paradoxical sleep hypersomnia following automatic paradoxical sleep deprivation. Three groups of mice were subjected to two periods of waking, one period of waking and one of paradoxical sleep hypersomnia, or two periods of paradoxical sleep hypersomnia. A high percentage of double-labelled neurons was observed in the lateral hypothalamic area and zona incerta of two periods of waking and two periods of paradoxical sleep hypersomnia in mice, but not in those of one period of waking and one of paradoxical sleep hypersomnia in animals. Melanin-concentrating hormone neurons in the lateral hypothalamic area and Lhx6+ cells in the zona incerta constituted 5.7 ± 1.5% and 8.8 ± 2.3% of all mCherry+ cells and 20.6 ± 4.8% and 24.6 ± 5.9% of all cFos+ neurons in two periods of paradoxical sleep hypersomnia in animals. In addition, melanin-concentrating hormone cells as well as Lhx6+ neurons rarely expressed mCherry (or cFos) in the waking condition, in contrast to orexin neurons, which constituted approximately 30% of mCherry+ and cFos+ neurons. Our results validate the TRAP methodology and open the way to use it for identifying the neurons activated during waking and paradoxical sleep hypersomnia. Furthermore, they indicate for the first time that Lhx6+ neurons in the zona incerta, like melanin-concentrating hormone cells in the lateral hypothalamic area, are activated during paradoxical sleep hypersomnia but not during waking. These results indicate that Lhx6+ neurons might play a role in the control of paradoxical sleep, like the melanin-concentrating hormone cells.
Subject(s)
Disorders of Excessive Somnolence/genetics , LIM-Homeodomain Proteins/metabolism , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Transcription Factors/metabolism , Animals , Disease Models, Animal , Male , Mice , Models, Genetic , Sleep Deprivation/metabolismABSTRACT
Importance: Insomnia, hypersomnia, and an evening chronotype are common in individuals with bipolar disorder (BD), but whether this reflects shared genetic liability is unclear. Stratifying by BD subtypes could elucidate this association and inform sleep and BD research. Objective: To assess whether polygenic risk scores (PRSs) for sleep traits are associated with BD subtypes I and II. Design, Setting, and Participants: This case-control study was conducted in the United Kingdom and Sweden with participants with BD and control participants. Multinomial regression was used to assess whether PRSs for insomnia, daytime sleepiness, sleep duration, and chronotype are associated with BD subtypes compared with control participants. Affected individuals were recruited from the Bipolar Disorder Research Network. Control participants were recruited from the 1958 British Birth Cohort and the UK Blood Service. Analyses were repeated in an independent Swedish sample from August 2018 to July 2019. All participants were of European ancestry. Exposures: Standardized PRSs derived using alleles from genome-wide association studies of insomnia, sleep duration, daytime sleepiness, and chronotype. These were adjusted for the first 10 population principal components, genotyping platforms, and sex. Main Outcomes and Measures: Association of PRSs with BD subtypes, determined by semistructured psychiatric interview and case notes. Results: The main analysis included 4672 participants with BD (3132 female participants [67.0%]; 3404 with BD-I [72.9%]) and 5714 control participants (2812 female participants [49.2%]). Insomnia PRS was associated with increased risk of BD-II (relative risk [RR], 1.14 [95% CI, 1.07-1.21]; P = 8.26 × 10-5) but not BD-I (RR, 0.98 [95% CI, 0.94-1.03]; P = .409) relative to control participants. Sleep-duration PRS was associated with BD-I (RR, 1.10 [95% CI, 1.06-1.15]; P = 1.13 × 10-5) but not BD-II (RR, 0.99 [95% CI, 0.93-1.06]; P = .818). Associations between (1) insomnia PRS and BD-II and (2) sleep-duration PRS and BD-I were replicated in the Swedish sample of 4366 individuals with BD (2697 female participants [61.8%]; 2627 with BD-I [60.2%]) and 6091 control participants (3767 female participants [61.8%]). Chronotype and daytime-sleepiness PRS were not associated with BD subtypes. Conclusions and Relevance: Per this analysis, BD subtypes differ in genetic liability to insomnia and hypersomnia, providing further evidence that the distinction between BD-I and BD-II has genetic validity. This distinction will be crucial in selecting participants for future research on the role of sleep disturbance in BD.
Subject(s)
Bipolar Disorder/genetics , Genetic Predisposition to Disease/genetics , Sleep Wake Disorders/genetics , Sleep/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Disorders of Excessive Somnolence/genetics , Female , Genome-Wide Association Study , Humans , Interview, Psychological , Male , Middle Aged , Multifactorial Inheritance/genetics , Risk Factors , Sleep Initiation and Maintenance Disorders/genetics , Young AdultABSTRACT
BACKGROUND: Bainbridge-Ropers syndrome is a rare autosomal dominant genetic disorder. CASE CHARACTERISTICS: A 26-day-old neonate presented with feeding difficulties, excessive sleeping, and hirsutism over forehead and lumbosacral skin. OUTCOME: Whole-exome sequencing identified a novel nonsense mutation. MESSAGE: We report a novel mutation in a Chinese neonate with Bainbridge-Ropers syndrome.
Subject(s)
Codon, Nonsense , Craniofacial Abnormalities/diagnosis , Disorders of Excessive Somnolence/diagnosis , Muscle Hypotonia/diagnosis , Psychomotor Disorders/diagnosis , Transcription Factors/genetics , Craniofacial Abnormalities/genetics , Disorders of Excessive Somnolence/genetics , Failure to Thrive/diagnosis , Failure to Thrive/genetics , Female , Genetic Markers , Hirsutism/diagnosis , Hirsutism/genetics , Humans , Infant, Newborn , Muscle Hypotonia/genetics , Psychomotor Disorders/genetics , SyndromeABSTRACT
The regulatory network of genes and molecules in sleep/wakefulness remains to be elucidated. Here we describe the methodology and workflow of the dominant screening of randomly mutagenized mice and discuss theoretical basis of forward genetics research for sleep in mice. Our high-throughput screening employs electroencephalogram (EEG) and electromyogram (EMG) to stage vigilance states into a wake, rapid eye movement sleep (REMS) and non-REM sleep (NREMS). Based on their near-identical sleep/wake behavior, C57BL/6J (B6J) and C57BL/6N (B6N) are chosen as mutagenized and counter strains, respectively. The total time spent in the wake and NREMS, as well as the REMS episode duration, shows sufficient reproducibility with small coefficients of variance, indicating that these parameters are most suitable for quantitative phenotype-driven screening. Coarse linkage analysis of the quantitative trait, combined with whole-exome sequencing, can identify the gene mutation associated with sleep abnormality. Our simulations calculate the achievable LOD score as a function of the phenotype strength and the numbers of mice examined. A pedigree showing a mild decrease in total wake time resulting from a heterozygous point mutation in the Cacna1a gene is described as an example.
Subject(s)
Genetic Testing/methods , Sleep/genetics , Wakefulness/genetics , Animals , Calcium Channels, N-Type/genetics , Computer Simulation , Crosses, Genetic , Disorders of Excessive Somnolence/genetics , Ethylnitrosourea , Female , Genes, Dominant , Homozygote , Lod Score , Male , Mice, Inbred C57BL , Mutation/genetics , Pedigree , Phenotype , Reproducibility of ResultsABSTRACT
BACKGROUND: Obstructive sleep apnoea (OSA) is one of the major sources of the excessive daily sleepiness, cognitive dysfunction, and it increases cardiovascular morbidity and mortality. Previous studies suggested a possible genetic influence, based on questionnaires but no objective genetic study was conducted to understand the exact variance underpinned by genetic factors. METHODS: Seventy-one Hungarian twin pairs involved from the Hungarian Twin Registry (48 monozygotic, MZ and 23 dizygotic, DZ pairs, mean age 51 ± 15 years) underwent overnight polysomnography (Somnoscreen Plus Tele PSG, Somnomedics GMBH, Germany). Apnoea hypopnea index (AHI), respiratory disturbance index (RDI) and oxygen desaturation index (ODI) were registered. Daytime sleepiness was measured with the Epworth Sleepiness Scale (ESS). Bivariate heritability analysis was applied. RESULTS: The prevalence of OSA was 41% in our study population. The heritability of the AHI, ODI and RDI ranged between 69% and 83%, while the OSA, defined by an AHI ≥5/h, was itself 73% heritable. The unshared environmental component explained the rest of the variance between 17% and 31%. Daytime sleepiness was mostly determined by the environment, and the variance was influenced in 34% by the additive genetic factors. These associations were present after additional adjustment for body mass index. CONCLUSION: OSA and the indices of OSA severity are heritable, while daytime sleepiness is mostly influenced by environmental factors. Further studies should elucidate whether close relatives of patients with OSA may benefit from early family risk based screening.
Subject(s)
Diseases in Twins/genetics , Disorders of Excessive Somnolence/genetics , Genetic Predisposition to Disease/genetics , Sleep Apnea, Obstructive/genetics , Sleepiness , Adult , Aged , Diseases in Twins/diagnosis , Diseases in Twins/epidemiology , Disorders of Excessive Somnolence/diagnosis , Disorders of Excessive Somnolence/epidemiology , Female , Genetic Predisposition to Disease/epidemiology , Humans , Hungary/epidemiology , Male , Middle Aged , Polysomnography/methods , Sleep Apnea, Obstructive/diagnosis , Sleep Apnea, Obstructive/epidemiologyABSTRACT
Objective/Background: The impact of midday napping on neurocognitive function in adolescents has not been well established. This study aimed to investigate the relationship between self-reported midday-napping behaviors and neurocognitive function in early adolescents. Participants: The sample was comprised of 363 early adolescents (12.00 ± 0.38 years old) from Jintan, China. Methods: Midday napping, nighttime sleep duration, and sleep quality were measured by self-reported questionnaires. Neurocognitive function was measured by the Penn Computerized Neurocognitive Battery (accuracy and reaction times). Generalized linear regression was used to analyze the relationships. Results: Sixty-four percent of our sample took more than 3 naps per week, and 70.11% reported nap durations of over 30 min. Participants with higher frequencies or longer durations of midday napping reported significantly better nighttime sleep quality (p < 0.05). Adjusted models showed that frequent nappers (5-7d/week) were significantly associated with heightened accuracy on tasks that measured sustained attention and nonverbal reasoning and faster reaction times on spatial memory compared with other frequency groups (ps < 0.05). For napping duration subgroups, early adolescents who took naps of any length were estimated to have faster reaction speeds on the sustained attention task compared with participants who never napped (ps < 0.05). However, only nappers with a moderate duration (31-60 min) tended to achieve both faster speeds (ß = -38.28, p = 0.02) and better accuracy (ß = 3.90, p = 0.04) on the sustained attention task. Conclusions: Our findings suggest that there is an association between habitual midday napping and neurocognitive function in early adolescents, especially in China, where midday napping is a cultural practice.