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  3. The Genetic Basis of Sleep and Sleep Disorders
  • Cited by 2
  • Edited by Paul Shaw, University of Washington, St Louis, Mehdi Tafti, University of Lausanne, Michael J. Thorpy, Sleep-Wake Disorders Center, Albert Einstein College of Medicine, New York
Publisher:
Cambridge University Press
Online publication date:
November 2013
Print publication year:
2013
Online ISBN:
9781139649469
DOI:
https://doi.org/10.1017/CBO9781139649469
Subjects:
Psychiatry and Clinical Psychology, Neurology and Clinical Neuroscience, Medicine, Psychiatry
Information

Book description

The first comprehensive book on the subject, The Genetic Basis of Sleep and Sleep Disorders covers detailed reviews of the general principles of genetics and genetic techniques in the study of sleep and sleep disorders. The book contains sections on the genetics of circadian rhythms, of normal sleep and wake states and of sleep homeostasis. There are also sections discussing the role of genetics in the understanding of insomnias, hypersomnias including narcolepsy, parasomnias and sleep-related movement disorders. The final chapter highlights the use of gene therapy in sleep disorders. Written by genetic experts and sleep specialists from around the world, the book is up to date and geared specifically to the needs of both researchers and clinicians with an interest in sleep medicine. This book will be an invaluable resource for sleep specialists, neurologists, geneticists, psychiatrists and psychologists.

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Contents

Page 2 of 2

Contents
  • Chapter 20 - Sleep and long-term memory storage
    pp 208-218
  • View abstract

    Summary

    This chapter discusses traditional metabolic genes that contribute to sleep regulation as well as candidate genes that may govern the systems independently. Inadequate sleep simultaneously modulates the level of multiple hormones that govern metabolism. In general, with sleep deprivation, the following hormones are decreased: insulin, growth hormone (GH), growth hormone releasing hormone (GHRH), and leptin levels. Even though starvation appears to confer fewer detrimental effects with extended waking than sleep deprivation, this response may come with consequences of its own. There are increasing number of proteins that affect sleep and metabolism, but are not classical metabolic genes. One class of genes that links metabolism and sleep is the circadian rhythm genes. It is interesting to note how often the effect of sleep deprivation invokes a starvation-like response from the body and how a starvation or a starvation-like state results in decreased sleep.
  • Chapter 21 - Sleep and synaptic homeostasis
    pp 219-226
  • View abstract

    Summary

    This chapter reviews different approaches and their findings in pursuit of sleep genes, with a highlight on the complex nature of sleep genetics revealed by those approaches. The polygenic nature of sleep can be appreciated even in studies using single-gene approaches. A branch of forward genetics, quantitative trait locus (QTL) analysis is the choice for comprehensively elucidating the genetic landscape of complex phenotypes such as sleep. The systems genetics approach, on the other hand, identifies genes whose expression affects sleep-wake phenotypes, and thus the genes identified are likely components of the sleep regulatory machinery and not simply a response to changes in sleep-wake states. Using multiple genetic approaches over the last few decades, researchers have begun to elucidate the genetic basis of sleep, and in particular, have established multigenic nature of sleep.
  • Chapter 22 - Heritability and genetic factors in chronic insomnia
    pp 227-234
  • View abstract

    Summary

    Forward genetic approaches led to the discovery of the first mammalian gene, Clock, to be identified at the molecular level in the core circadian clock. The persistence of clock function when only one paralog is removed is fairly common in the molecular clock system; however, few genes seem to be completely redundant when genome-wide transcript and transcription technologies were implemented it became clear that between 2% and 10% of all genes were expressed with a near 24-h rhythm, and each of these is not considered as a core clock gene, where the transcription/translation feedback loop is the basis of many observed behavioral and cellular rhythms, there are some molecular circadian rhythms that can oscillate independently of transcription. Investment into development of drugs that can treat sleep, mood, and metabolic disorders using the gears of the molecular clock are well underway.
  • Chapter 23 - HLA and narcolepsy
    pp 235-241
  • View abstract

    Summary

    This chapter provides an overview of the chief epigenetic mechanisms: DNA cytosine methylation and hydroxymethylation, histone protein post-translational modifications (PTMs) and higher-order chromatin remodeling, non-coding RNA (ncRNA) regulation, and RNA editing. High level of 5-methylcytosine (5mC) is found in gene regulatory regions and generally associated with transcriptional repression. This occurs because DNA methylation inhibits the transcriptional machinery from accessing DNA. Chromatin is implicated in a broad range of processes including transcriptional regulation, X chromosome inactivation (XCI), genomic imprinting, DNA replication and repair, and the maintenance of genomic integrity. RNA editing events can alter amino acids encoded by corresponding genomic DNA, alternative splicing patterns, and regulatory sequences and their associated interactions. Preliminary data suggest that DNA methylation is modulated by circadian rhythms. DNA methylation at specific genomic loci can play a role in the pathophysiology of sleep disorders.
  • Chapter 24 - Orexin (hypocretin)and narcolepsy
    pp 242-253
  • View abstract

    Summary

    This chapter reviews the genetics of sleep and its most widely used correlate, the electroencephalogram (EEG), in mice and humans. Monozygotic (MZ) and dizygotic (DZ) studies allow measurement of genetic and environmental contributions to a trait. Reverse genetic approaches involve isolation of candidate genes, use of transgenic models, and phenotypic analysis of mutant animals. The first quantitative trait locus (QTL) mapping study for sleep amounts identified several genomic regions associated with the amount of rapid eye movement (REM) sleep. For the identification of genes involved in sleep, large-scale analysis of gene expression by microarrays has been performed in rats and mice. Microarray studies allow better understanding of how gene expression changes as a function of duration of wakefulness. A mutagenesis screen in mice is underway and might turn out to be successful in finding major genes regulating sleep duration as well as EEG.
  • Chapter 26 - Genetic disorders producing symptomatic narcolepsy
    pp 260-271
  • View abstract

    Summary

    This chapter reviews the experimental evidence for an association between the circadian and the homeostatic phases of sleep regulation at the molecular level. Variability in the dynamics of the sleep homeostat could be expected to contribute to modifications in the habitual sleep duration and in the sensitivity to increased sleep pressure. As in the mouse, the factors contributing to differences of the dynamics of sleep homeostasis are likely to be genetic. The first line of evidence that supports a role of clock genes in sleep homeostasis involves the observation that elevated sleep pressure changes the expression of clock genes in various brain areas. Clock genes respond to increased neuronal activity and influence synaptic plasticity and the expression of synaptic elements determining synaptic strength. The increasing knowledge on the homeostatic regulation of the various aspects of sleep has led to hypotheses concerning sleep's still elusive functions.
  • Chapter 27 - Genetics of recurrent hypersomnia
    pp 272-278
  • View abstract

    Summary

    This chapter reviews the approaches that have been used to identify genomic variation that may shape circadian entrainment and point new directions of research. It addresses some issues concerning study designs that may increase the efficiency of finding genetic components of the circadian clock in human. If the inter-individual differences in human time-of-day preference or in chronotype are extreme, they can manifest themselves as familial syndromes. The application of ethnicity markers is meanwhile a routine strategy in genome-wide association (GWA) studies. The GWA strategy is more reliable than a candidate gene approach. Human entrainment to different photoperiods may involve substantial plasticity in individual circadian period and phase of entrainment. High-throughput analyses are applied in circadian rhythms research. The authors have recently applied high-throughput genomics to identify alleles associated with phase of entrainment in extreme chronotypes.
  • Chapter 28 - Linkage and candidate gene studies of obstructive sleep apnea
    pp 279-301
  • View abstract

    Summary

    This chapter provides a brief description of the main animal models used in the study of sleep and cognition, which reveals their intercomplementary strength and scope. Two types of sleep deprivation are commonly carried out in rodents: total sleep deprivation (TSD) and rapid eye movement (REM) sleep deprivation (RSD). Memory consolidation during sleep could be a passive and unselective process due to a prolonged quiet period without any flow of information. The study of sleep-dependent cognitive processes is relatively recent in birds and few studies have so far included sleep deprivation. Sleep deprivation protocols include gentle handling, placing birds in a running wheel, the disc-over-water method, and constant light. Drosophila serves as a model system for the investigation of many cellular, developmental, and behavioral processes common to other species, including humans.
  • Chapter 29 - Genomic variants and genotype–phenotype interactions in pediatric sleep-related breathing disorders
    pp 302-312
  • View abstract

    Summary

    During sleep deprivation, the homeostatic sleep drive does not build up as high in the long sleepers as in the short sleepers due to allostatic effects from prior sleep history, and at least in part as a consequence of genetic make-up, there are large individual differences in the cognitive deficits caused by sleep deprivation. A frequently overlooked aspect of trait vulnerability to sleep loss is that ranking of individuals in terms of magnitude of their vulnerability depends on the task they perform. Despite an ongoing, worldwide search for predictors of trait vulnerability to sleep loss, reliable biomarkers have not yet been identified. Handful of genetic polymorphisms has been found to modulate individual vulnerability to sleep deprivation. In summary, healthy adults exhibit systematic individual differences both in sleep duration and in cognitive impairment due to sleep loss.
  • Chapter 30 - Genetics offamilial advanced sleep phase
    pp 313-326
  • View abstract

    Summary

    Diurnal preference for sleep-wake timing and activity is well known and can be quantified by simple questionnaires. A consistent finding across different studies is that there tends to be increased morning preference in women compared to men of same age. About 50% of variance in diurnal preference is heritable, so it should be expected that differences in diurnal preference should be associated with underlying genetic variation. A primate-specific, variable number tandem repeat (VNTR) polymorphism in the coding region of PER3 is associated with diurnal preference and also delayed sleep phase disorder. Diurnal preference is a complex/heterogeneous phenotype that shows high level of heritability. It is directly related to intrinsic circadian function and determined by the interaction of the circadian pacemaker and the sleep homeostat. Roughly half of the variance observed in diurnal preference is heritable while the remainder is presumably determined by environmental factors.
  • Chapter 31 - Delayed sleep phase disorder, circadian genes, sleep homeostasis and light sensitivity
    pp 327-334
  • View abstract

    Summary

    This chapter focuses on long-term memory and its relationship to sleep with an emphasis on the role of sleep during memory consolidation. Declarative memory consolidation relies on the reactivation of the initially labile memory traces in the hippocampal formation as the temporary store, which drives memory reactivation in the cortex for long-term storage. Procedural memory of acquired skills is most often tested with regard to the effects of sleep. Regions critical for the consolidation of procedural memory are the cerebellum, striatum and motor cortex. Aside from pure memory consolidation, an added consideration for emotional memory is the effect of sleep on emotional salience. Long-term memory is dependent on the various sleep stages for consolidation. Aging is accompanied by general decline in memory and cognitive function. Many neurodegenerative diseases have profound deficits on systems critical for long-term memory consolidation and sleep regulation.
  • Chapter 32 - Family and genome-wide association studies of restless legs syndrome
    pp 335-350
  • View abstract

    Summary

    Sleep could promote many forms of synaptic plasticity, independent of whether the underlying mechanism is synaptic depression or synaptic potentiation. Memory consolidation and brain restitution are important perspectives on the function of sleep that are not mutually exclusive. Synaptic homeostasis hypothesis (SHY) reconciles these two perspectives by proposing that the main function of sleep is to control the strength of synapses impinging on neurons in the cerebral cortex and elsewhere. Most evidence supporting SHY is correlative, and has been collected in one tissue, the cerebral cortex. As sleep is most abundant early in life, and the brain undergoes massive synaptic turnover during neurodevelopment, with an early phase of net synaptogenesis followed by net pruning, it is important to ask whether sleep could benefit synaptic renormalization during this phase of enormous plasticity.
  • Chapter 33 - Circadian clock genes and psychiatric disorders
    pp 351-364
  • View abstract

    Summary

    This chapter focuses on advances towards heritability and genetic approaches in insomnia disorders in human. Insomnia remains a heterogeneous condition that is primarily characterized and diagnosed by subjective complaints about dissatisfaction with sleep quantity or quality, and it is not associated with any specific biomarker. Some of the first twin studies with a focus on insomnia suggest the involvement of genetic factors in early-onset (childhood) insomnia. The first familial study on insomnia using a clinic based sample suggests the presence of familial insomnia aggregations, especially among individuals with childhood or adolescence onset compared to those with adult onset. Twin studies strongly suggest that genetic factors may trigger insomnia with genetic effects accounting for approximately one-third of the variance in insomnia complaints. Results from twin studies suggest that heritability would potentially account for large proportion of variance in insomniac symptoms.
  • Chapter 35 - Gene therapy for sleep disorders
    pp 375-380
  • View abstract

    Summary

    This chapter reviews the contribution of the human leukocyte antigen (HLA) molecule in narcolepsy in terms of genetic association, relationship to clinical characteristics, autoimmune hypothesis and molecular mechanisms. The HLA genotype has been related to sleep, even in healthy subjects. In 1983, a strong association was reported in Japanese narcolepsy patients with HLA. Narcolepsy is not limited to the core symptoms of lapsing into sleep and cataplexy, but also exhibits wide range of associated symptoms that are somatic and neuropsychiatric. Among known HLA-related diseases, the relative risk of narcolepsy is extremely high. Although, there is no direct evidence for autoimmunity, studies of environmental factors in narcolepsy have suggested that previous infectious diseases could be a trigger to develop narcolepsy. Association with the HLA complex is not limited to narcolepsy, and over 100 types of diseases are known to show significant associations with HLA.

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