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This chapter discusses the methodological considerations surrounding linkage and association studies as well as results of both approaches as they relate to sleep and sleep disorders. The initial study of familial advanced sleep phase syndrome (FASPS) that showed it to be inherited in an autosomal dominant fashion was a linkage study on a large family with over 20 affected individuals. For the most part, the risk of narcolepsy to relatives of an affected individual is low (1-2%), albeit higher than the average population risk. Restless leg syndrome (RLS) is fairly common, with the prevalence estimated to be between 1.2 and 15% depending on the population. Complex phenotypes are influenced by multiple genetic and non-genetic factors. These phenotypes cluster in families do not follow any clear mode of inheritance. Complex phenotypes are divided into two classes: continuous and categorical. Genome-wide association study (GWAS) has been recently employed in studying sleep phenotypes.
There has been a significant increase during the last decades in knowledge of genetics of sleep and sleep disorders, and the genetic epidemiologic studies have considerably contributed to this progress in understanding their basis. The primary goal of genetic epidemiology is the resolution of the genetic architecture of a trait, such as sleep length or a disorder. Electroencephalogram (EEG), a parameter included in polysomnography (PSG), has been found to be one of the most heritable characteristics, with heritability estimates greater than 95%, in a sample of 10 MZ and 10 DZ twin pairs. Most studies indicate that certain sleep problems in childhood are largely influenced by genes. Most parasomnias are relatively common to very common in childhood, occurring clearly less frequently in adults. Clinical experience and many studies indicate that parasomnias are often found to co-occur and run in families.
Understanding how sleep-wake schedules are biologically determined via cellular circadian rhythmicity may reveal potential treatments for circadian rhythm sleep disorders (CRSDs). Familial advanced sleep phase (FASP) is the first human Mendelian circadian rhythm trait to be identified. FASP is expected to exhibit an autosomal dominant mode of inheritance, and phenotyping and obtaining DNA from related individuals aids genetic analysis. As self-reported data are subjective, physiological circadian rhythm measurements are crucial for supporting self-reported data. With the advent of high-throughput genotyping methods and growing knowledge of circadian components, novel genetic variants can now be identified through both recombination mapping and candidate approaches. Animal models remain essential for proving genetic causation, especially for evaluating behavioral traits such as sleep-wake timing. This chapter discusses a practical framework for investigating the human genetic basis of sleep and other complex behaviors.
This chapter describes the different approaches that might be taken to elucidate the genes conferring risk for obstructive sleep apnea (OSA) and for its downstream consequences. Linkage studies are useful for investigating patterns of genetic marker and phenotype co-transmission in affected families. Overall, linkage analysis has not proven, to date, to be a successful approach for discovery of sequence variants that contribute to risk of OSA or severity of the condition. Many association studies of OSA-associated traits, such as obesity, have been undertaken and several association studies of OSA have been performed. OSA is most likely very polygenetic with many gene-gene interactions given what we know already about many different risk factors. Current approaches have been largely limited to linkage studies and candidate gene association studies. Genome-wide association studies (GWAS) will likely and only lead to identifying a limited part of the heritability of OSA.
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.
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.
In order to better understand the different roles genetic factors can play in restless legs syndrome (RLS), it is important to recognize that RLS can be a primary disorder or secondary to a number of other medical conditions, such as iron deficiency, pregnancy, and renal failure. To date, three genome-wide association studies (GWAS) have been performed for RLS and one for RLS and periodic limb movements in sleep (PLMS). Both family and association studies have implicated candidate genomic regions and candidate genes in RLS. With respect to GWAS, genetic heterogeneity is exemplified by the fact that the currently identified association signals only account for approximately 6.8% of the projected heritability although they confer relatively large risk increases. RLS is a genetically complex disease and this complexity is probably not only marked by locus heterogeneity but also by the range of different variants likely to be involved.
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.
This chapter reviews the sleep and circadian rhythms disturbances observed in psychiatric disorders, as well as their possible associations with circadian clock genes. Recent studies have provided interesting data on associations between clock gene polymorphisms and major depressive disorders (MDD). Seasonal affective disorder (SAD) is another common mood disorder, affecting around 10% of the population living in temperate latitudes. Bipolar disorder (BPD) is a complex disorder arising from the inheritance of multiple genetic variants in which patients alternate between episodes of mania and depression. Schizophrenia affects about 1% of the general population. It is a complex and severe psychiatric disorder characterized by profound disruptions of cognition, emotion and social functions. In the last decade, there has been mounting evidence to suggest that circadian rhythm deficits play a key role in most psychiatric disorders.
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.
Gene therapy has been used successfully to treat some intractable diseases. It has also been used in neurodegenerative diseases. The neuropeptides hypocretins (HCRT), also known as orexins, were discovered by two independent groups using different approaches. In 2000, examination of post-mortem tissue has revealed loss of the HCRT neurons in the brains of subjects with narcolepsy. Now it is abundantly clear that narcolepsy is neurodegenerative disease, as other markers that colocalize with HCRT are also absent in human with narcolepsy. In the case of narcolepsy there are two valid animal models of human narcolepsy, which permit hypothesis-driven testing of the efficacy of the gene transfer methodology. One can foresee that light stimulation of specific circuits will be used to manipulate behavior such as sleep, tremors in Parkinson's disease, or memory of fearful events in post-traumatic stress disorder.
This chapter focuses on the neuroimaging of cataplexy using a case of a 68-year-old woman, who had suffered from narcolepsy since she was 15 years old, as an example. Her mean sleep latency during a multiple sleep latency test was 0.5 minutes, with three sleep onset rapid eye movement (REM) periods among the four naps. The patient underwent two 99mTc-ethylcysteinate dimer brain single-photon emission computed tomography (SPECT) studies during symptomatic and asymptomatic periods of cataplexy on two non-consecutive days. Symptomatic SPECT images were coregistered with asymptomatic images and both images were then co-registered with 3-dimensional magnetic resonance imaging (MRI). The normalized subtracted SPECT and MRI volumes were merged for visual analysis. A characteristic of human REM sleep is right-hemisphere activation, as shown by SPECT imaging and spectral electroencephalographic (EEG) analysis. The right hemisphere is also more activated during cataplexy than the left hemisphere.
This chapter reviews the techniques currently applied to study brain function during sleep deprivation (SD) as opposed to the consequence of SD. It provides a bird's eye view of functional imaging studies performed on healthy young adult volunteers to date and comment on how this research has evolved the conceptualization of how SD modulates behavior. The first functional imaging studies involving SD utilized positron emission tomography (PET). Based on the initial findings, cognitive domain and task difficulty was proposed as determinants of the neural response to SD. It was postulated that changes in dopamine signaling in the SD state contributed to the change in functional connectivity, an idea reprised when discussing risky decision making in SD. The interaction of SD and circadian effects, including the effects of chronotype, could be a further target of functional neuroimaging studies, including the effect of countermeasures such as naps and stimulants.
Numerous findings of brain structural changes in obstructive sleep apnea (OSA) give strong support to the notion that the disorder does cause brain injury. This chapter describes findings by technique, influences of factors other than the sleep disordered breathing on structural changes in OSA, and a summary of the brain regions shown across multiple studies to be affected in the disorder. Psychological symptoms of depression and anxiety are associated with neural changes in non-OSA populations, so one can hypothesize that the structural changes in OSA would be exacerbated in the presence of these symptoms. Many areas in the brain show structural impairments in OSA, including cortical, limbic, brainstem and cerebellar regions. Neuroimaging methods give numerical measures that are associated with a variety of biological pathologies, and technical limitations due to scanning and analysis issues limit the interpretability of the data.