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The genetics of sleep 

The genetics of sleep
The genetics of sleep

Alexandra Sousek

, and Mehdi Tafti

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date: 19 February 2020

Why hunt for genes involved in sleep?

The obvious variation of sleep phenotypes within the human population and their intra-individual stability, as well as familial aggregation of certain sleep-related disorders, led to the hypothesis that sleep might be influenced by genetic background. A multitude of twin studies and familial analyses on the prevalence and transmission of sleep traits suggested a genetic contribution to various aspects of sleep and its disturbances. In particular, the human sleep EEG was found to be strongly influenced by genetic factors, which is consistent with the finding that the human EEG in general is a highly heritable trait [1,2]. However, modulations by age, gender, and environmental factors remain to be fully determined. For a summary of twin studies, see Table 5.1, and for findings drawn from familial studies, see Table 5.2.

Table 5.1 Genetic contribution to sleep phenotypes

Sleep trait

Estimated heritability


Sleep duration



Sleep quality



Sleep efficiency and wake after sleep onset

50% and 42%, in males only


Sleep onset latency

High sign correlation in MZ only


Sleep architecture, stage changes, frequency profiles

  • Higher concordance in MZ than DZ, sign correlation in MZ

  • 96%


  • NREM sleep characteristics

  • (frequency profile, stage 2 amount, stage 3/4 amount (SWS), spindle density)



  • REM sleep characteristics

  • (patterns, amount, density)



Diurnal preference



Neurobehavioral reaction to sleep loss






RLS and related symptoms



Sleep-talking, bruxism, enuresis

  • 54–70% in children

  • 48–53% in adults


Table 5.2 Familial and linkage studies


Mode of inheritance

Involved molecules or loci


Familial advanced sleep phase syndrome (FASPS)

Autosomal dominant

hPer2, CK1ɛ, and CK1δ‎


Restless legs syndrome (RLS)

Autosomal dominant

  • 12q: RLS1

  • 14q: RLS2

  • 9q: RLS3 and RLS3*

  • 2q: RLS4

  • 20p: RLS5

  • 19p



Autosomal recessive

12q: RLS1




  • 12q: RLS2

  • 14q: RLS2



Primary nocturnal enuresis (PNE)

Autosomal dominant

  • 4q

  • 12q

  • 13q: ENUR1

  • 22q: ENUR3


Twin studies

Early twin studies already found a higher concordance of sleep habits, such as sleep duration and quality, in monozygotic (MZ) than in dizygotic (DZ) twins, even when they were living apart and thus exposed to different environments [3,4,5]. The first polysomnographic recordings revealed concordant temporal sleep patterns in terms of sleep stages in MZ [6]. Since then, many twin studies have been performed to untangle the impact of dominant or additive genetic influences and shared or nonshared environmental factors on the various aspects of sleep. Genetic background was proposed to contribute substantially to sleep duration, quality, onset latency and efficiency, diurnal preference, sleep structure, and characteristics of NREM sleep such as amount of sleep stages 2 and 4, delta/slow-wave sleep (SWS), and spindle density, as well as REM sleep and wake after sleep onset (see Table 5.1) [6,7,8,9,10,11,12,13]. While findings on REM sleep remain controversial, NREM sleep is found consistently to be under strong genetic control in humans and mice [1,8,14,15]. REM sleep amount was found to be significantly correlated in MZ twins, and REM density was estimated to be up to 95% heritable in some studies, although others found no such relation [6,8,9,10,11]. Genetic influence on NREM sleep is well established. Even a genetically determined “individual fingerprint” of NREM sleep structure has been proposed, according to which an individual can be reliably distinguished from others, irrespective of sleep pressure as assessed by sleep deprivation studies [16,17,18]. Further, theta, delta, alpha, and sigma frequency bands of the wake and NREM sleep EEG were more significantly correlated in MZ than DZ twins [19].

Different aspects of sleep homeostasis, as assessed by effects of sleep deprivation, were found to be under genetic control in humans and mice. Franken et al. were able to show in various inbred mouse stains that delta activity rebound after sleep deprivation, and thus that processes of sleep homeostasis are under strong genetic control [14]. Supporting Van Dongen’s claim that human neurobehavioral response toward sleep loss was an inter-individual trait-like characteristic, the neurobehavioral reaction toward sleep deprivation was determined as a highly heritable trait, in that decline in vigilance is significantly more similar in MZ than in DZ twins [13,20]. Since increases in slow-wave activity (SWA) and delta power during NREM sleep of recovery after sleep loss are well-established markers for sleep homeostasis in humans, twin studies recording EEGs during and after sleep deprivation could further elucidate the heritability of these homeostatic processes [21].

Another important aspect of sleep that has been intensively investigated is subjective sleep quality, mainly assessed by the Pittsburgh Sleep Quality Index (PSQI). Substantial heritability of up to 44% was estimated in several studies [5,22]. Further, with 94% association, a strong overlap of genetic influence on sleep quality and diurnal preference was determined, suggesting common underlying mechanisms [22].

In dyssomnias and parasomnias, higher concordance and thus estimated heritability rates were found in MZ compared with DZ twins (see Table 5.1). Parasomnias comprise atypical behavior or physiological events occurring during specific sleep periods, such as sleepwalking or enuresis, while dyssomnias are characterized by unusual amount, quality, or timing of sleep. A study on 100 MZ and 199 DZ 8-year-old twin pairs estimated 71% of genetic contribution to variability for dyssomnias and 50% for parasomnias [23]. Studies on insomnia revealed up to 57% estimated heritability, whereas distinctive symptoms such as “trouble staying asleep” were found to be differentially modulated by genetic background or gender [24,25,26]. Likewise, in sleepwalking, genetic effects were estimated to account for 80% of variability in males and 36% in females [27]. Sleep-related breathing disorders and their associated disabling symptoms such as excessive daytime sleepiness were found to be heritable in up to 52% of cases [28]. Other conditions with substantial genetic contribution are enuresis, bruxism, sleep-talking, and restless legs syndrome [28,29,30,31,32].

Familial studies and linkage analysis

Certain sleep-related diseases show high familial risk and specific modes of transmission (see Table 5.2). Linkage studies using microsatellite markers and phenotypes, testing for co-segregation and inheritance patterns, aim to define chromosomal regions conferring risk and susceptibility to the development of a disease, and thus provide help to find the underlying genetic factors. This can contribute to the development of appropriate treatments, risk assessment, and prevention. In the following, the potential of such studies will be demonstrated on the examples of familial advanced sleep phase syndrome, restless legs syndrome, and primary nocturnal enuresis.

Familial advanced sleep phase syndrome

Familial advanced sleep phase syndrome (FASPS) shows an autosomal dominant pattern of inheritance with high penetrance. Since this disease is characterized by early bedtime and early morning awakening, it is not surprising that links to genes underlying circadian rhythmicity have been found. In a linkage analysis, a specific haplotype of the human period (PER2) gene was found co-segregating with FASPS [37]. Within this haplotype, an A-to-G transition leads to substitution of a conserved serine by glycine. This missense mutation alters binding of casein kinase 1ε‎ (CK1ε‎) to the Per2 protein and thus its phosphorylation. Further, a mutation in the gene encoding CK1δ‎ (CSNK1D) itself can be causal for the disease. Screening an FASPS kindred for mutations, a T-to-A transversion in a highly conserved sequence of CSNK1D was detected, which co-segregates with the disease [38]. This missense mutation entails a threonine-to-alanine substitution leading to a decrease in enzymatic activity and phosphorylation. Accordingly, animal models carrying this mutation showed similar affected circadian phenotypes.

Restless legs syndrome

Restless legs syndrome (RLS) is suggested to be a polygenetic disease, with high familial vulnerability and an estimated heritability of 50%, whereas the involved genetic regions and their mode of inheritance remain controversial, indicating high heterogeneity and complexity [39,40,41]. Linkage studies of affected families revealed six associated loci on chromosomes 12q, 14q, 9p, 2q, 20p, and 6p termed RLS1–6, but without characterization of the responsible genes [40,42,43,44,45,46,47,48,49]. Autosomal dominant transmission was mainly suggested for RLS2 and RLS3, and in families with early onset of the disease, while RLS1 was repeatedly found to be recessive [40,42,44,50,51].

Loci on chromosome 9 (RLS3 and possibly RLS3*) were consistently found important [8,43,44,45], while for other loci findings remained more controversial. Bonati et al. reported linkage to a locus on 14q (RLS2) and co-segregation in an autosomal dominant manner, while others could not confirm this in several French-Canadian families [48,52]. Desautels et al. were able to define a 14.71 cM region on chromosome 12q (RLS1) conferring susceptibility to the disease in an autosomal recessive way in a large French-Canadian family. This is especially interesting, since neurotensin (NTS) is encoded in that region and acts as neuromodulator of dopaminergic transmission, which has repeatedly been associated with RLS [49]. This putative connection is strongly supported by the observed relief of symptoms upon treatment with dopamine agonists [42]. However, sequencing of this gene in four affected families revealed two polymorphisms in the intronic region and one in the 5′ UTR, but no co-segregation with the disease [53]. In contrast to the findings by Desautels et al. Kock et al. determined autosomal dominant transmission concerning the 12q locus in two South Tyrolean families [54]. Further analyses in 19 affected families confirmed autosomal recessive transmission in some, and thus the involvement of another crucial locus was suggested [50]. The complexity and heterogeneity of the etiology of this disease are also supported by findings of a study assessing linkage of RLS1, RLS2, and RLS3 in 12 Bavarian families, where neither clear proof nor disproof of linkage could be determined using parametric linkage analysis [55].

Xiong in 2007 investigated the possible influence of divalent metal transporter 1 (DMT1), which is a good candidate, given the reduced iron levels in the brains of affected individuals, the association with anemia, and the location of the gene on chromosome 12q, close to the RLS1 locus. Cell culture techniques showed no difference in protein levels in blood cells of patients and controls. Neither a linkage between the DMT1 gene region and RLS nor any underlying mutations within the gene region were found. However, two single nucleotide polymorphisms (SNPs) in the intronic region were associated with the disease in patients with anemia [56].

More recently, further regions conferring susceptibility have been identified by applying genome-wide association analysis (GWAS). Winkelmann et al. determined highly significant associations between the disease and intronic variants of MEIS1 (homeobox) on 2p, BTBD9 (POZ domain) on 6p, and a locus containing the MAP2K5 (kinase) and LBOXCOR1 (transcription factor) genes on chromosome 15q [57]. Accordingly, Stefansson found a common intronic variant of the BTBD9 gene significantly associated with the disease and responsible for 50% of risk in this population [58]. Intriguingly, this was accompanied by decreased serum ferritin levels, since RLS is considered to be associated with disturbed brain iron metabolism [42,58]. This region on chromosome 6p21 is also referred to as RLS6 [40]. Recently, in a genome-wide linkage analysis including affected families from eight European countries, a novel region significantly linked to RLS in an autosomal dominant manner was detected [59]. However, mutations in the genes of interest located in that area could not be found.

Primary nocturnal enuresis

Linkage analyses concerning primary nocturnal enuresis (PNE) have revealed involvement of regions on chromosomes 12q, 13q (ENUR1), and 22q (ENUR3) [60,61,62,63]. Intriguingly, within the confined region on chromosome 12q, the aquaporin-2 water channel is encoded, but the transitions found did not lead to functional alteration of the protein [62]. More recently, a new locus on chromosome 4 has been found to segregate with nocturnal enuresis and incontinence with high penetrance. This region on 4p16 contains the dopamine receptor genes DRD5 and D1B, which might be good candidates [64].

Effects of genetic variation on sleep

To understand the contribution of genetic variation and involved molecular pathways to sleep phenotypes and the development of disease, association to, and thus assumed influence of, naturally occurring SNPs and variable number of tandem repeats (VNTRs) have been extensively studied. This has indeed led to a considerable amount of knowledge being obtained about the factors involved, but the picture is not complete, and the interaction and mutual influence of involved pathways remain unclear and require further study. For an overview of genetic variations affecting sleep phenotypes, see Table 5.3.

Table 5.3 Genetic variations affecting sleep phenotypes



Affected phenotype/trait



SNP, missense mutation

Sleep architecture, SWS and delta power, reaction to sleep deprivation




EEG frequencies in sleep and wake, sensitivity to caffeine, vigilance, reaction to sleep deprivation




Sleep quality, depression, RLS, narcolepsy controversial



Missense mutation

SWS, reaction to sleep deprivation, sensitivity to modafinil, narcolepsy symptoms




Reaction to sleep deprivation, sensitivity to caffeine


HTR2A (5-HT2A receptor)


Risk for OSA


SLC6A4 (5-HTT)

Insertion/deletion variant

Risk for primary insomnia and sleep quality


GABRA (GABAA receptors)

Missense mutation

Primary insomnia



Missense mutation

NREM frequencies, SWS, reaction to sleep deprivation, working memory



SNPs in promoter and coding region

Association with narcolepsy, partly dependent on HLA type



Missense mutation

Association with narcolepsy



Missense mutations

Trigger of FFI/CJD and modulation of phenotype



Missense mutation in signal peptide

Severe early onset narcolepsy with cataplexy



VNTR, SNPs in promoter region,

Diurnal preference, sleep latency, DSPS, reaction to sleep deprivation


PER2 and CSNK1

Missense mutations




SNP in 5′ UTR

Diurnal preference


Adenosinergic neurotransmission

Adenosinergic neurotransmission is suspected to play a major role in the regulation of sleep and wakefulness and their homeostasis in mice and humans [14,66]. Common genetic variants affecting different aspects of sleep homeostasis in healthy humans support this hypothesis. A functional SNP on the human chromosome 20q13.11 changes a guanine (G) to adenine (A) in the adenosine deaminase (ADA) enzyme. Asparagine (in the ADA*1 variant) is changed into aspartic acid (in the ADA*2 variant), which results in lower enzymatic activity and thus less adenosine degradation in heterozygous G/A (ADA*1–2) carriers compared with G/G (ADA*1). Concerning sleep, Retey et al. found an increase in slow-wave sleep (SWS) during an undisturbed night in ADA*1–2 carriers resembling the effects of one night of sleep deprivation. This was further accompanied by higher delta power in NREM sleep, which is a marker of sleep need [67,68]. Also, the response to sleep deprivation was found to be modulated by this genotype, with elevated SWS and delta activity in NREM sleep of recovery nights after 40 hours of prolonged wakefulness in ADA*1–2 subjects [67]. Thus, it is assumed that reduced enzymatic activity due to genetic variability leads to enhanced build-up of sleep pressure.

Among adenosine receptors, it is mainly subtypes A1 and A2A that are considered important in sleep regulation [66]. The thymine (T)-to-cytosine (C) transition in the coding region of the A2A receptor gene (ADORA2A) on chromosome 22q11.2 not only affects EEG activity, generally irrespective of sleep and wake, but also modulates the effects of its antagonist caffeine on sleep and sleep deprivation. Only C/C carriers show increases in high-frequency EEG after sleep deprivation. Further, the C-allele was found to confer sensitivity to caffeine-induced sleep disturbances [69]. Analysis of the effects of combinations of eight SNPs of the ADORA2A gene revealed that one haplotype (HT4) was associated with enhanced vigilance at the baseline, but resistance to caffeine-induced rescue of vigilance decline after sleep loss was observed in non-HT4 carriers. Likewise, caffeine had differential effects on SWS in recovery sleep that were dependent on genotype. While non-HT4 carriers showed reduced SWS upon caffeine administration, this effect was missing in HT4 individuals. The build-up of sleep pressure assessed by EEG and increase in subjective sleepiness were not affected [70].

Monoamine oxidase

Monoamine oxidase (MAO) A and B are encoded on the X-chromosome and catalyze the degradation of monoamines: the catecholamines dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine) and the tryptamines serotonin and melatonin. Thus, it is an important enzyme for the regulation of major neurotransmitters implicated in sleep. Females carrying an allele conferring higher activity due to a variable number tandem repeat (VNTR) polymorphism in the MAO-A promoter region are at higher risk of developing RLS [71]. Further, the less active allele seems to confer susceptibility to depression and poor sleep quality [72]. Koch et al. proposed an association of a VNTR in intron 1 of the MAOA gene and a dinucleotide repeat in intron 2 of the MAOB gene with the occurrence of narcolepsy with cataplexy [73]. This could not be confirmed by others, suggesting HLA type and gender as underlying causes for the difference [74]. However, MAO-A and -B inhibitors are capable of reducing symptoms of narcolepsy such as cataplexy and abnormal REM sleep [75,76].

Dopaminergic neurotransmission

A G-to-A transition in catechol-O-methyltransferase (COMT) entails a functional polymorphism resulting in a valine–methionine exchange. This leads to reduced activity of the dopamine-metabolizing enzyme and thus higher dopaminergic transmission. Indeed, Val/Val homozygous subjects show less dopaminergic signaling in their prefrontal cortex (PFC) than those carrying Met/Met [77]. Bodenmann et al. found no effects of this polymorphism on baseline sleep, while Goel observed differences in SWS decline [78,79]. In chronic partial sleep deprivation of five consecutive nights with 4 hours sleep, Val homozygotes showed smaller increase in SWS, while Met homozygotes had steeper SWS decline. This was accompanied by shorter REM sleep latency in Val/Val subjects [79]. Further, the commonly used stimulant modafinil, which promotes dopaminergic neurotransmission, was shown to be effective in terms of counteracting total sleep deprivation-induced impairments of attention and other cognitive functions in Val homozygotes only [80]. Val genotype enhanced certain NREM frequency bands during recovery sleep, but without changing slow-wave activity [78]. Thus, homeostatic processes as well as stimulant efficiency seem to be modulated by dopaminergic signaling, and this polymorphism might be of interest in stimulant treatments.

Dauvilliers et al. found no association between COMT genotype and narcolepsy, but an interaction of gender and genotype as well as a strong influence on severity of the disease independent of gender was observed [74]. Females homozygous for the less active allele as well as heterozygotes exhibit higher sleep latency than those homozygous for the highly active variant. The opposite effect was observed in males. Irrespective of gender, more sleep paralysis but less sleep onset REM periods were observed in heterozygous narcoleptic patients. HLA type was found not to interact with COMT genotype.

A crucial player in dopaminergic signaling is the dopamine transporter (DAT), whose blockage by modafinil results in elevated dopamine levels in the extracellular space. DAT knockout mice are insensitive to modafinil, but show increased consolidated wakefulness, less REM sleep, and hypersensitivity to caffeine [81]. In humans, a VNTR polymorphism in the 3′ UTR of the DAT-encoding gene SLC6A3 leads to less DAT in the striatum in individuals homozygous for the long 10-repeat allele as compared with carriers of the 9-repeat allele [82]. According to the animal data, 10/10 carriers are more sensitive to caffeine generally, as well as to its effect on reducing SWS rebound after sleep deprivation, which was found more pronounced in 10-repeat homozygotes [83].

Serotonergic neurotransmission

It is well established that serotonergic or 5-hydroxytryptamine (5-HT) activity promotes wakefulness and inhibits REM sleep. The serotonergic receptors 5-HT1–7 exert different functions according to their associated second messengers. Thus, postsynaptic cells can either be inhibited (5-HT1A and 5-HT1B) or depolarized (5-HT2A/2C, 5-HT3, and 5-HT7) upon receptor activation. Further, the outcome of their activation depends on their localization. Activation of 5-HT1A and 5-HT1B receptors expressed by GABAergic and of 5-HT3 receptors expressed by glutamatergic interneurons lead to disinhibtion and stimulation, respectively. On the other hand, activation of 5-HT2A/2C or 5-HT7 expressed by GABAergic interneurons leads to inhibition, and the activation of all receptor types leads to inhibition of cholinergic neurons. Within this complex system, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3, and 5-HT7 receptors have been shown to be involved in the regulation of wakefulness and REM sleep [84]. Mice lacking 5-HT1A or 5-HT1B receptors have more REM sleep than wild types, but unchanged wake and SWS [85,86]. 5-HT7 knockouts show lower amounts and fewer episodes of REM sleep [87]. 5-HT2 subunits were suspected to be implicated in NREM sleep regulation, and knockout of 5-HT2A or 5-HT2C leads to more wake, reduced NREM sleep, and abnormalities in REM sleep in mice [88,89].

In humans, polymorphisms in the gene HTR2A encoding the 5-HT2A receptor have been suspected to confer risk of obstructive sleep apnea (OSA), and functional binding of serotonin to 5-HT2A expressed on motor neurons of the upper airways is crucial to ensure proper respiration during sleep. Recent meta-analyses of studies investigating associations of a −1438G/A polymorphism in the promoter region of HTR2A and/or silent T102C polymorphisms with the risk of OSA found a significant association for the first only in that homozygosity for the A variant confers risk, especially in males [90,91].

Also, the serotonin transporter (5-HTT), which determines the amount of serotonin in the synaptic cleft, might be involved. A common 44 base-pair insertion/deletion variant in the regulatory 5′ region of the serotonin transporter gene SLC6A4 affects its expression and thus the abundance of 5-HTT at the synapse. An association study revealed that the short variant of this polymorphism is significantly more common in patients suffering from insomnia than in healthy controls [92]. Further, this polymorphism was proposed to mediate environmental effects such as chronic stress and stressful life events on sleep quality and length, respectively [93,94]. Nevertheless, another study found homozygosity for the long allele to be associated with poor sleep [95].

GABAergic neurotransmission

Several lines of evidence point to involvement of the main inhibitory neurotransmitter γ‎-aminobutyric acid (GABA) in the initiation of sleep, as well as in the etiology and maintenance of primary insomnia. Studies applying magnetic resonance spectroscopy found reduced GABA levels globally or in the occipital cortex and anterior cingulate cortex but not the thalamus of patients with primary insomnia [96,97]. Others detected elevated occipital cortical GABA levels and proposed that this was a countermeasure to hyperarousal [98]. Consistently, they found levels of GABA to be negatively correlated with the amount of wake after sleep onset [96,98]. Screening for mutations in ligand-binding domains of the α‎1, β‎3, and γ‎2 genes of the GABAA receptor revealed a heterozygous missense mutation in one patient with chronic insomnia. The substitution of arginine for histidine presumably entails reduced GABAergic inhibition [99].

Brain-derived neurotrophic factor

Evidence for the involvement of brain-derived neurotrophic factor (BDNF) in sleep–wake regulation was found in animal studies [14,100]. In a sleep deprivation study on six inbred mouse strains, a chromosomal region containing the gene encoding the BDNF receptor tyrosine kinase B (TrkB) determined 49% of variance in the build-up of sleep pressure [14]. In rats, BDNF secretion was suggested to be a mediator of sleep homeostasis [100]. In humans, a common functional polymorphism, a G-to-A transition, leads to amino acid substitution from valine to methionine and thus impaired activity-dependent secretion of the protein, which is implicated in synaptic plasticity and associated with cognitive performance [1]. Heterozygous carriers of the Met allele show decreased slow wave sleep and delta and theta power in NREM sleep during undisturbed nights, as well as after one night of sleep deprivation [101]. Likewise, in previous studies, impacts on cognitive function, i.e. working memory, were observed [101,102]. Thus, implication of this polymorphism in plasticity and regulation of sleep homeostasis is assumed.

Tumor necrosis factor

Tumor necrosis factor (TNF) α‎ is a pro-inflammatory cytokine involved in many processes and also proposed to be involved in sleep regulation. Evidence comes from observations that injection of TNF-α‎ in rodents dose-dependently increases NREM sleep and suppresses REM sleep [103,104,105]. Accordingly, disruption of its functionality by administration of anti-TNF-antibodies or creation of TNF receptor knockout mice lead to blockage of NREM sleep and sleep disturbances [105,106]. Since in humans several polymorphisms in the promoter region of the TNFA gene are known and linked to neurological and inflammatory diseases and the gene lies within the HLA class II cluster, it has become a target of interest in the pathophysiology of narcolepsy [107]. Indeed, narcoleptic patients show elevated plasma levels of TNF-α‎ and soluble TNF-α‎ receptor but no mutation either in TNFA or in TNF-α‎ receptor genes was detected [108,109,110,111]. Results for the numerous SNPs are inconsistent, partly owing to HLA type or ethnicity. In association studies, Hohjoh et al. found a SNP in the promoter region of TNFA significantly associated with narcolepsy independent of HLA haplotype DRB1*15:01 as well as an association of disease with a polymorphism in the TNF receptor 2 gene (TNFR2) that leads to exchange of a methionine with an arginine [112,113]. Wieczorek et al. found a C857T polymorphism in TNFA associated with narcolepsy, but only in DRB1*15/16-negative German patients, while no such link was detected in a Taiwanese study [107,108]. The SNPs C863A and G308A of TNFA and a microsatellite adjacent to the gene were not found to be linked to narcolepsy independent of HLA in a German sample [107]. Likewise T-1031C, C-863A, and a SNP leading to a missense mutation in TNFR2 were found not to be associated in the Taiwanese population [108].

Prion protein

Fatal familial insomnia (FFI) is a highly penetrant hereditary disease transmitted in an autosomal dominant manner. FFI is characterized by disrupted sleep, i.e., loss of sleep spindles and SWS, and impaired sleep stage organization, as well as progressive reduction of sleep time. This goes along with reduced metabolism in thalamic and limbic regions and degeneration of thalamic nuclei. Investigation of two Italian affected kindred revealed an underlying point mutation in the prion protein (PrP) gene (PRNP) on chromosome 20. A missense mutation, a G-to-A transition at codon 178, leads to substitution of aspartate for asparagine [114,115]. Creutzfeldt–Jakob disease (CJD) is characterized by the same mutation and accumulation of protease-resistant prion protein plaques, but differs from FFI regarding a polymorphism at codon 129, which is common and leads to either incorporation of a methionine or valine, and further to protein isoforms differing in size and glycosylation pattern [116]. While in FFI-affected individuals the mutated allele encodes for methionine, those with CJD express valine on the mutated PRNP allele [117]. Studies on further kindred confirmed the influence of the 129 polymorphism on the expressed phenotypes of the different prion-related diseases [115].


Neurons expressing the neuropeptides hypocretin-1 (HCRT-1) and -2 (HCRT-2), also termed orexin A and B, which are processed from their common precursor prepro-hypocretin (HCRT), are exclusively found in the lateral hypothalamus. They have widespread projections throughout the brain, such as the cortex and pons, and are involved in the arousal system. Two receptors (HCRTR-1 and HCRTR-2) have been defined up to now. Several lines of evidence point toward involvement of deficiency in this system in narcolepsy. In humans, reduced levels of HCRT-1 in cerebrospinal fluid (CSF) and several brain regions and deficiency of prepro-hypocretin mRNA in the hypothalamus, as well as loss of orexin-producing cells, have been documented [118,119,120]. In dogs, an autosomal recessive mutation in the Hcrtr2 gene causes narcolepsy, and mice that lack prepro-hypocretin show symptoms of the disease [121,122]. Consequently, intensive screening for human mutations has been performed. Neither a common C-to-T polymorphism in HCRT nor a previously reported polymorphism in its 5′ UTR were found to be associated with narcolepsy in a study with 105 families [123]. This holds also for 14 defined polymorphisms in hypocretin receptors, although normal CSF levels of HCRT-1 found in some patients point toward receptor defects [119]. Similarly, there are families lacking HCRT-1 in the CSF without mutations in the HCRT gene and delayed onset of disease [119]. To date, only one functional polymorphism is known, found in a patient with severe cataplexy and unusually early onset of the disease. A G-to-T transversion leads to a change in the signal peptide of HCRT, where a highly charged arginine is introduced in a hydrophobic polyleucine stretch of the peptide, which alters trafficking and impairs cleavage. The attempt to assign this as a de novo mutation failed because DNA was only available from the unaffected mother but not the unaffected father [119].

The strong association of the disease with HLA allelic variants led to the hypothesis of autoimmune destruction of hypothalamic hypocretin neurons [124]. Enriched tribbles homologue 2 (TRIB2), which can serve as an autoantigen, in hypocretin-producing neurons of a transgenic mouse model, as well as elevated levels of TRIB2-specific antibodies in serum of narcoleptic patients corroborate this theory [125,126]. However, the exact underlying mechanism of the destruction of orexin-producing cells remains unknown.

A recent study showed that the re-expression of orexin receptors on noradrenergic neurons in the locus coeruleus and on serotonergic neurons in the dorsal raphe nuclei of orexin receptor knockout mice could rescue symptoms of narcolepsy [127]. Intriguingly, the amount of restored orexin signaling on serotonergic neurons correlated with the observed reduction in cataplexy, and that on noradrenergic neurons correlated with reduced fragmentation of wakefulness [127]. This suggests a crucial interaction of different neurotransmitter systems in the pathophysiology of narcolepsy.

Circadian “clock” genes

In mammals, a transcription–translation feedback loop serves as the basic mechanism for the clock machinery in the suprachiasmatic nucleus (SCN) to control circadian rhythmicity. Briefly, the basic helix–loop–helix PAS transcription factors CLOCK and BMAL1 form the heterodimer BMAL1/CLOCK (alternatively BMAL1/NPAS2), which binds to E-Box elements of promoters and induces transcription of, among others, the cryptochrome 1 and 2 (CRY1 and CRY2) and period (PER1–3, PER3 only in humans) genes and the gene encoding the nuclear receptor Rev-Erbα‎ (NR1D1). The PER and CRY proteins, in turn, act as negative regulators of CLOCK/BMAL1 activity by forming a repressor complex with casein kinase (CK) 1ε‎ (encoded by the CSNK1E gene) and CK1δ‎ (CSNK1D). Rev-Erbα‎ represses transcription of CLOCK and BMAL1 [128,129,130]. Besides their function in circadian rhythmicity, clock genes have also been found to influence sleep variables. Supporting evidence comes from animal models showing that knockout of BMAL1 and NPAS2 and double knockout of Cry1 and Cry2 lead to abnormalities in sleep homeostasis in mice [131,132,133,134].

One of the most intensively studied “clock” genes is the human period 3 (PER3) gene on chromosome 1. PER3 polymorphism has repeatedly been associated with diurnal preference and delayed sleep phase syndrome (DSPS) [135,136,137,138]. A VNTR in the coding region leads to either a short or a long allele; PER34 or PER35, respectively. Homozygosity for the longer variant PER35/5 is consistently found to be associated with morningness, and homozygosity for PER34/4 with eveningness. This variation further influences sleep latency, amount of SWS, and differences in recovery from sleep deprivation. Individuals homozygous for the long allele (PER35) show more SWS in NREM and more alpha activity in REM sleep, earlier wake and bed times, and less daytime sleepiness, as well as a more intense response to sleep deprivation regarding cognitive decline and reduced brain activation when performing executive tasks, especially in the early morning [138,139,140]. Other studies applying chronic partial sleep deprivation found an effect of the polymorphism on sleep homeostasis but not on cognitive performance [141]. Several further polymorphisms of PER3 were defined and associated with DSPS [142]. Four haplotypes consisting of five polymorphisms in the coding region were investigated and one haplotype was found to be significantly associated with the disease. Functionally, the glycine incorporated into the protein instead of a valine in that haplotype was suggested to alter phosphorylation of the PER3 protein by CKIɛ. Further, the majority (75%) of patients suffering from DSPS were found to carry the PER34/4 variant, which is associated with eveningness [136]. A study investigating the promoter region of PER3 revealed two SNPs that were more prevalent in DSPS patients compared with either morning or evening types of the healthy control subjects and thus could contribute to the disease by changing the expression levels [135]. As described in the section on FASPS earlier in this chapter, altered phosphorylation of PER2 due to a missense mutation of CK1 or its binding site is involved in FASPS [37,38].

In 1998 Katzenberg found a T3111C polymorphism in the 3′ UTR of CLOCK associated with diurnal preferences, in that carriers of the C allele are more often evening-type [143]. Since then, controversial replications of that finding have been reported. In a Japanese sample, the highest eveningness was likewise found in C/C homozygous subjects, together with significantly delayed sleep onset, shorter sleep duration, and higher daytime sleepiness compared with either heterozygous or homozygous T-allele carriers.[144]. On the contrary, studies performed in Caucasian and Brazilian subjects found no association with either diurnal preference or DSPS [145,146].

Concluding remarks

The genetics of sleep, as opposed to all other complex traits, is still at its inception. Although progress has been made in demonstrating that most sleep phenotypes and sleep disorders are controlled by genetic factors, very few causal genetic factors have been discovered. Sleep is controlled at too many levels, from molecular to organismic behavioral level. So far, almost all candidate genes have been shown to affect sleep, adding to the complexity of this behavior. Whether single genes play an essential role remains elusive. Sleep disorders represent ideal models to uncover the molecular pathways that are critically involved. Nevertheless, examples from other fields strongly indicate that the best way to gain further insight must include both basic research and translational research, linking disorder phenotypes to normal mechanisms regulating the most basic biological substrates.


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