Genetic Aspects of Sleep in Humans Aspectos Genéticos Do Sono Em Humanos

Guindalini C, Tufik S 125

REVIEW

Genetic aspects of sleep in humans Aspectos genéticos do sono em humanos

Camila Guindalini1, Sergio Tufik1

ABSTRACT were estimated for the delta, theta, alpha, and beta frequency (3) Together with the environment, genetic factors can significantly bands, respectively, in all tested areas of the brain . More re- influence sleep and its architecture. Monozygotic twins have cently, De Gennaro et al.(4) showed that the EEG pattern in the greater similarity in terms of latency and duration of sleep cycles 8-16 Hz range is far more similar in MZ twins than in dizygotic than dizygotic twins, in addition to almost identical spectral (DZ) twins. With a heritability estimate of 96%, this EEG pat- patterns. These observations indicate a genetic contribution to tern is considered one of the most heritable traits in humans. sleep regulation and suggest that inter-individual variations in its parameters may be associated with genetic modulators. With the These findings show the extraordinary contribution of genet- advent of techniques and molecular-genetic approaches, a number ics to normal sleep regulation and suggest that inter-individual of genetic factors have been systematically identified that appear variations observed in sleep parameters may be associated with to contribute to the large variability observed in the normal sleep genetic modulators. patterns of individuals and to a greater predisposition to the development of sleep disorders. This review aims to address the main scientific discoveries on the genetics of sleep in humans, GENETIC FACTORS INVOLVED IN HUMAN presenting an overview of the current situation and future prospects SLEEP in this constantly evolving area. Clock genes Keywords: genetics, genome, sleep. A growing number of studies have attempted to identify candidate genes underlying the wide inter-individual variability RESUMO observed in sleep parameters and related phenotypes(5). The as- Estudos recentes têm demonstrado que fatores genéticos podem, sociation between a common variant observed in the period-3 em conjunto com o ambiente, influenciar o sono e sua arquitetura (PER3) gene and diurnal preference is possibly the most widely de maneira significativa. Gêmeos monozigóticos apresentam maior studied genetic polymorphism in the field of sleep (Table 1). similaridade em termos de latência e duração dos ciclos do sono, The PER3 gene, together with the PER1, PER2, CLOCK, and além de padrões espectrais praticamente idênticos, quando com- brain and muscle Arnt-like protein 1 (BMAL1) genes, among parados aos gêmeos dizigóticos. Essas observações evidenciam a contribuição genética na regulação do sono e sugerem que varia- others, is part of a set of genes regulating the mammalian cir- ções interindividuais em seus parâmetros podem estar associadas a cadian timing system. This system consists of protein transcrip- fatores genéticos moduladores. Com o advento das técnicas e abor- tion and translation feedback loops, with positive and negative dagens da genética molecular, uma série de fatores genéticos têm elements. The CLOCK and BMAL1 proteins unite to form a sido sistematicamente identificados, os quais parecem contribuir heterodimer, which is responsible for promoting the transcrip- tanto para a ampla variabilidade observada no sono normal do in- divíduos, como para uma maior predisposição ao desenvolvimento tion of PER1, PER2, PER3, and the cryptochrome genes CRY1 de distúrbios do sono. Essa revisão pretende abordar as principais and CRY2. In turn, proteins encoded by these genes combine in descobertas científicas acerca do tema da genética do sono em hu- the cytoplasm and form a complex that returns to the nucleus manos, apresentando um panorama da situação atual e das perspec- and blocks the action of the CLOCK/BMAL1 heterodimer, tivas futuras em uma área em constante evolução. which ultimately inhibits the transcription of its own genes in a Descritores: genoma, genética, sono. negative-feedback loop that lasts approximately 24 hours. The described process is the basis of the circadian rhythmicity(6). GENETICS AND SLEEP In humans, the PER3 gene presents a repeat polymor- Sleep is a complex behavior characterized by interac- phism in which a region of 54 base pairs may be repeated four 4/4 4/5 tions between genetic and environmental factors(1,2). In humans, or five times, producing the genotypes PER3 , PER3 , and 5/5 among the biological factors that contribute to the large indi- PER3 . In 2003, Archer et al. showed that the long five-repeat vidual variability observed in sleep parameters, studies in twins allele of the repeat polymorphism in the PER3 gene was as- indicate a significant participation of genetic factors. A study sociated with diurnal preference, whereas the short four-repeat assessing the sleep of 213 pairs of twins, with a mean age of allele was more common in individuals classified as evening in- (7) 16 years, observed that monozygotic (MZ) twins show great dividuals, according to the Horne-Ostberg questionnaire . Fur- similarity in all frequency bands of the electroencephalogram thermore, the study also showed that 75% of individuals with (EEG). Indices of heritability of 76%, 89%, 89%, and 86% delayed sleep-phase syndrome (DSPS), a disorder that results

Study carried out at Departamento de Psicobiologia - Universidade Federal de São Paulo - SP. Brazil. 1 Departamento de Psicobiologia - Universidade Federal de São Paulo - SP. Brazil. Corresponding author: Camila Guindalini. Rua Napoleão de Barros, nº 925. Vila Clementino. São Paulo - SP. Brazil. CEP: 04021-002. Phone: 55 (11) 2149-0155. Fax: 55 (11) 5572-5092. E-mail: [email protected] Received: April 26, 2012; Accepted: July 23, 2012.

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Table 1. Review of the genes associated with sleep disorders or phenotypes, with results replied at least once in an independent sample and/or confirmed in functional assays. Sleep phenotype Identified gene References Sleep Apnea Tumoral Necrosis Factor - alpha (TNF-α) Varvarigou et al. 201141 Narcolepsy Human Leucocyte Antigen (HLA) (DQB1*0602) Mignot et al. 199819 T Cell Receptor Alpha Locus (TRA-alfa) Hallmayer et al. 200921 Carnitine Palmitoyl Transferase 1B (CPTB1) Miyagawa et al. 200822 Choline Kinase Beta (CHKB) Miyagawa et al. 200822 Human Leucocyte Antigen (HLA) (DQA2) Hor et al. 201023 Purinergic Receptor, Subtype P2Y11 (P2RY11) Kornum et al. 201124 Restless legs syndrome BTB (POZ) domain-containing 9 (BTBD9) Stefansson & Winkelmann et al. 200726, 27 Myeloid ecotropic viral integration site homeobox 1 Winkelmann et al. 200727 (MEIS1) Mitogen activated protein kinase kinase 5 (MAP2K5) Winkelmann et al. 200727 Ladybird homeobox co-repressor 1 (LBXCOR1) Winkelmann et al. 200727 Receptor-type tyrosine-protein phosphatase delta Schormair et al. 200833 (PTPRD) TOX high mobility group box family member 3 Winkelmann et al. 201135 (TOX3) Non-coding RNA BC034767 Winkelmann et al. 201135 Familial Advanced Sleep Phase Syndrome Period 2 (PER2) Toh et al. 200110 Casein Kinase 1 delta (CKI-delta) Xu et al. 200512 Familial Delayed Sleep Phase Syndrome Period 3 (PER3) Archer et al. 20037, Pereira et al. 20058 Short Sleepers DEC2 He et al. 200913 Diurnal Preference Period 3 (PER3) Archer et al. 20037, Pereira et al. 20058 Sleep length ATP-binding cassette, sub-family C- 9 (ABCC9), Allebrandt et al. 201114 Sleep Homeostasis Adenosine Deaminase (ADA) Rétey et al.200517, Mazzotti et al. 201115

in symptoms similar to insomnia (presenting difficulty waking taneous awakening in the early morning. A genetic study con- up at the desired time in the morning) were homozygous for ducted on a family with multiple FASPS individuals found an the short allele (PER34/4). A subsequent study in Brazil con- association between a region of chromosome 2q and the pres- firmed the increased propensity for eveningness in subjects with entation of FASPS. Following this initial finding, the region was the short allele(8) and showed that, unlike a previous study con- sequenced, and a mutation of the candidate gene PER2 was ducted in England, the long five-repeat allele is associated with identified in all affected members of the family(10). This muta- DSPS(8), indicating that the difference in latitude could influence tion causes a serine-to-glycine change specifically in the region the effects of clock genes. where the PER2 protein is phosphorylated. In a subsequent Studies conducted on healthy subjects have also shown study, Xu et al.(11) showed that the insertion of the human muta- that PER3 gene polymorphism appears to be related not only tion in transgenic mice generated a phenotype similar to FASPS, to diurnal preference but also to the homeostatic regulation where animals showed a marked advance in their rest-activity of sleep(9). Compared to individuals homozygous for the four- cycle. This study confirmed the functionality of the mutation repeat allele (PER34/4), people with the PER35/5 genotype have found in the family. The importance of the phosphorylation a worse cognitive performance after a period of sleep depri- of proteins involved in maintaining the biological rhythm was vation. Furthermore, a series of markers of sleep homeostasis reinforced by another study, in which a mutation in the casein is increased in people with PER35/5, including slow-wave sleep, kinase I delta (CSNK1D) gene, also responsible for the phos- rapid eye movement (REM) sleep, and alpha and theta activity phorylation of the clock genes, was found in a second family during wakefulness(9). with FASPS(12). Familial advanced sleep-phase syndrome (FASPS), an Another rare, large-effect mutation influencing sleep autosomal-dominant disorder, is characterized by an episode of duration was identified in the DEC2 gene, a transcriptional re- early sleep, with an onset at the early evening hours and spon- pressor, in a small family with the early-awakening phenotype(13).

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The DEC2 gene is also a clock gene that negatively regulates the type(19). However, this effect was only evident in subjects who mechanism of circadian rhythm. The identified mutation, which consumed coffee on the day of the polysomnography. No effect causes the amino acid proline to be substituted with arginine in was observed in the absence of coffee. Our data support the role the protein, was found in two women (mother and daughter) of the G22A polymorphism and the ADA gene in sleep regula- who, despite initiating sleep at the same time as other individu- tion and suggest that caffeine can modulate its functional effects als in the family, presented a much earlier awakening, with an (Table 1). average duration of 6.25 hours of sleep. These individuals, considered natural “short sleepers”, report shorter total sleep dura- GENETIC FACTORS INVOLVED IN SLEEP tion than patients with FASPS or control individuals, without DISORDERS it negatively affecting their daily routine(13). Studies conducted Narcolepsy on transgenic mice carrying the mutation confirmed that these Narcolepsy is a recognized familial sleep disorder. The animals present shorter sleep duration than wild-type animals. concordance rate between monozygotic twins is ~30%, which Moreover, the mutation confers a significant reduction in sleep suggests the involvement of genetic factors, in addition to en- rebound after a period of sleep deprivation, suggesting that vironmental factors, in its development(20). The allele known as even though the DEC2 gene is considered a clock gene, it also DQB1*0602, located in the human major histocompatibility seems to be involved in the homeostatic processes of sleep(13). complex (HLA), is considered a genetic marker strongly related A recent study used functional measures to evaluate to an increased risk for developing narcolepsy, particularly in seven European populations (N = 4,251) in a genome-wide as- Caucasian subjects. This allele is present in up to 95% of pa- sociation study (GWAS), an impartial technique to study com- tients with cataplexy in this ethnic group, compared to a fre- plex genetic diseases by simultaneously analyzing approximately quency of ~24% in the general population(15), which confirms 500,000 to 1 million polymorphisms distributed throughout the the complexity of narcolepsy and the involvement of multiple genome(14) (Figure 1). In this GWAS, Allebrandt et al. identified genes in its manifestation. a variant (rs11046205) in the ATP-binding cassette, sub-family Due to the strong association with the HLA complex C-9 (ABCC9) gene, which appears to explain ~5% of the inter- and the fact that patients with narcolepsy and cataplexy present individual variation related to sleep duration. Individuals ho- a reduction or absence of orexin (hypocretin) in the cerebro- mozygous for the variant slept approximately 30 minutes longer spinal fluid and in the number of orexin cells in the lateral hy- than individuals without the genetic variant. The ABCC9 gene pothalamus, an autoimmune etiology for narcolepsy has been encodes a subunit of the ATP-dependent potassium channel suggested; however, this etiology has not been confirmed, even (SUR2) and serves as an intracellular energy sensor. Further- after decades of research(20). Recent results from GWASs have more, SUR2 participates in the etiology of cardiomyopathies, offered new scientific support for this hypothesis (Table 1). disorders that are closely related to body mass index and hyper- In a study involving a total of 807 cases, all positive for the tension, which are endophenotypes correlated with the dura- DQB1*0602 allele, and 1,074 Caucasian controls, Hallmayer et tion of sleep. Experiments using RNA interference showed that al.(21) used microarray technology to evaluate > 500,000 poly- when the gene homologous to ABCC9 in Drosophila neurons morphisms and the risk for developing narcolepsy. In this ini- was knocked down, the animals did not sleep during the first 3 tial phase, positive associations were observed with three SNPs, hours of the night. These results provide more consistent evi- all located in the locus of the alpha chain of the T-cell recep- dence regarding the involvement of ABCC9 in the regulation tor (TRA-alpha), which, together with proteins from the HLA of sleep duration. system, participates in the process of antigen recognition. As occurs in GWASs, the results were subjected to replication in Adenosine deaminase different ethnic groups and confirmed in a second sample of Caffeine, a widely consumed stimulant, induces wakeful- Caucasians and a sample of 866 Japanese and 300 Koreans, but ness and blocks adenosine receptors, resulting in the inhibition not in a smaller sample of African American individuals, most of its endogenous activity(15). Several recent lines of evidence likely due to the low statistical power of the latter(21). confirm that the activation of A1 and A2A adenosine receptors In 2008, Miyagawa et al.(22) reported an association be- and the regulation of adenosine production and degradation are tween a marker located between the carnitine palmitoyltrans- essential for sleep induction and adequate control of the sleep- ferase 1B (CPT1B) and choline kinase beta (CHKB) genes and wake cycle(16). The gene that encodes the enzyme adenosine the risk for narcolepsy with cataplexy in a Japanese population. deaminase (ADA), responsible for the conversion of adenosine The results were replicated in an independent sample of Japa- to inosine, contains a G/A single-nucleotide polymorphism nese individuals as well as a sample of Koreans, but not in Euro- (SNP) at nucleotide 22 of exon 1 (G22A), whose A allele leads to peans or African Americans, most likely due to lower frequencies the substitution of asparagine for aspartic acid in the protein(17). of the risk allele in these two populations. Still, the meta-analysis The enzymatic activity of ADA is 20-30% lower in erythrocytes including all ethnic groups showed significant results, with the and lymphocytes of individuals with a G/A genotype, highlight- risk allele being associated with an almost two-fold increase in ing this polymorphism as a potential marker for adenosinergic the risk for developing narcolepsy. Furthermore, the expression homeostatic regulation of sleep(18). Interestingly, in 2005, Rétey levels of both genes were reduced in individuals carrying the risk et al.(17) reported that healthy carriers of the gene variant had allele compared to individuals with two non-risk alleles. Plausi- a greater duration and intensity of slow-wave sleep and fewer ble biological explanations support the participation of CPT1B awakenings. Corroborating these findings, our group has recently and CHKβ in the pathophysiology of narcolepsy. CPT1B is a shown that individuals carrying the A allele (with a G/A or A/A rate-limiting enzyme for the beta-oxidation of long-chain fatty genotype) have a higher sleep efficiency and greater percentage acids in muscle mitochondria. Carnitine transport, an important of REM sleep compared to individuals with the G/G geno- step in fatty acid oxidation, plays an important role in pheno-

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Figure 1. Experimental design used in Genome-Wide Association Studies (GWAS). In a primary case-control sample, the DNA from hundreds of individuals is subjected to microarray assays, in which thousands of Single Nucleotide Polymorphisms (SNPs) are analyzed simultaneously. After the statistical analysis and correction by multiple tests, only the SNPs the fill the selection criteria are re-analyzed in one or more replication samples for confirmation in despite of results due to ethnic differences.

types related to narcolepsy. The enzyme CHKβ is involved in Restless legs syndrome the synthesis of cytidine 5’-diphosphocholine, which seems to Restless legs syndrome (RLS) has familial and sporadic increase the release of acetylcholine, a neurotransmitter known presentations. Cases of early onset (before the age of 30) are to promote wakefulness and REM sleep(22). often familial, whereas secondary causes include pregnancy, In 2010, Hor et al.(23) conducted a GWAS accompanied renal failure subject to dialysis, and iron deficiency(5). The first by an independent replication sample in heterozygous individuals approach to identify genes involved in the development of for the haplotype DRB1*1501-DQB1*0602. The results showed the disease initially included studies of family links. Although a significant association with a variant near the HLA-DQA2 locus chromosome regions 14q, 9p, 2q, 20p, and 19p were identified (rs2858884), which is closely related to DRB1*03-DQB1*02 and as regions of interest, no specific genes or mutations were DRB1*1301-DQB1*0603. Surprisingly, patients with narcolepsy identified(25). Instead, in 2007, two nearly simultaneous GWASs rarely presented the haplotype DRB1*1301-DQB1*0603 (odds on RLS published consistent findings of great scientific value ratio = 0.02; p < 6×10−14), which suggests a highly protective ef- (Table 1). fect of the identified variant and confirms the importance of the The first study, evaluating an Icelandic population con- HLA locus in the development of narcolepsy. sisting of 306 cases and > 15,000 controls, found a significant More recently, a third GWAS with replications in three association between an intronic SNP located in the gene BTB different ethnic groups (3,406 individuals with European ances- (POZ) domain-containing 9 (BTBD9) and an increased risk of try, 2,414 Asians, and 302 African Americans) reported a positive ~50% for the manifestation of RLS associated with periodic leg relationship between narcolepsy and a SNP located in the 3’-un- movement(26). This result was replicated in a second phase, in an

translated region of the gene that encodes the P2Y11 subtype of independent sample of Icelanders and a sample of American the purinergic receptor (P2RY11)(24). The allele variant associated individuals. Moreover, the risk allele variant was associated with with increased risk for developing narcolepsy showed a significant lower levels of ferritin, corroborating the previously described correlation with reduced expression of the P2RY11 gene and re- risk factor for RLS, iron deficiency. sistance of T lymphocytes and natural killer cells to cell death. Using a different approach for subject selection, Win- These results highlight the P2RY11 gene as an important regula- kelmann et al.(27) published a second GWAS involving only tor of immune cell survival and, together with the study by Hall- patients with a clear family history of RLS in an attempt to mayer et al.(21), provide extremely robust data that strengthen the reduce the phenotypic heterogeneity. When evaluating more autoimmune hypothesis in the pathophysiology of narcolepsy. than 4,000 individuals, associations with SNPs located in the Sleep Sci. 2012;5(4):125-130

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following regions were identified: the BTBD9 gene on chromo- on OSAHS. Therefore, in contrast to narcolepsy and RLS, the some 6p (replicating the findings of the previous study), the progress in determining the genetic basis of OSAHS has been myeloid ecotropic viral integration site homeobox 1 (MEIS1) slower. gene on chromosome 2p, and a third region in chromosome The genetic involvement in the development of OSAHS 15q that contains the genes mitogen-activated protein kinase ki- is indisputable(37). It has been estimated that up to 40% of the nase 5 (MAP2K5) and ladybird homeobox co-repressor 1 (LBX- total variance observed for the apnea/hypopnea index in family COR1). A subsequent study in an American sample replicated members can be attributed to genetic factors(37). A study evaluat- the association between RLS and the MEIS1 and BTBD9 genes ing a total of 1,937 pairs of twins showed that the correlation only(28). The association of BTBD9 with sporadic and familial between MZ twins is significantly greater than that of DZ twins RLS was verified in a European sample of individuals from the for the symptoms of apnea, with indices of heritability that Czech Republic, Austria, and Finland. However, the contribu- range from 48% (95% confidence interval: 37-58%) for day- tions of the MEIS1 and MAP2K5/LBXCOR1 genes were only time sleepiness to 52% (95% confidence interval: 36-68%) for confirmed in familial cases of RLS(29). snoring(38). Redline et al.(39) estimated the level of familial aggre- Little is known about the biological functions of the gation for a number of OSAHS symptoms. Habitual snoring, identified genes and their relationships with RLS. MAP2K5 is excessive daytime sleepiness, and apnea were reported two to a protein kinase, and LBXCOR1 inhibits LBX1, which is a ho- four times more often among first-degree relatives of patients meobox gene involved in sensory pathways in the dorsal horn with OSAHS compared to control individuals(39). A number of of the spinal cord(27). Both BTBD9 and MEIS1 have been as- variants in candidate genes have been examined in the search sociated with the embryonic development of the limbs(30,31). for genetic markers that may influence the risk of developing An independent study has shown a reduction in the levels of OSAHS. Significant associations with OSAHS or any related MEIS1 mRNA and protein in peripheral blood and in post mor- phenotype were observed in the angiotensin-converting enzyme tem samples of the thalamus of subjects with the risk allele of (ACE), apolipoprotein E (APOE), endothelin receptor subtype the gene(32), suggesting that a reduced function of this protein A (EDNRA), endothelial nitric oxide synthase (NOS3), tumor may contribute to the pathogenesis of RLS. necrosis factor alpha (TNF), interleukin 6 (IL6), and seroton- Using a different approach, Schormair et al.(33) performed ergic system genes, among others(40). However, most of the a detailed analysis involving 3,270 SNPs located exclusively in studies mentioned above require replications of independent the chromosome 9p region and found strong evidence of an samples, with a large numbers of individuals of different eth- association between RLS and two SNPs, both in the protein nic origins, before being considered true susceptibility markers. tyrosine phosphatase receptor delta (PTPRD) gene, in German, Furthermore, no GWAS has been published on OSAHS, which Czech, and Canadian patients. Studies conducted on knock-out limits the results to genes and variants that are already known mice revealed that PTPRD plays an important role in neuronal and are hypothetically part of the pathophysiology of the dis- development and axonal direction(34). ease. One of the great advantages of the GWAS is that it is a Winkelmann et al.(35) reported the results of a GWAS relatively hypothesis-free approach, which enables the discovery that included more than 12,000 individuals. The authors repli- of new risk factors not previously associated with the pheno- cated previously observed significant associations between the type of interest. More recently, a meta-analysis accompanied by development of RLS and the loci in MEIS1, BTBD9, PTPRD, a systematic literature review on sleep apnea genetics reported and MAP2K5/SKOR1 and reported two new susceptibility loci that only four polymorphisms had been investigated, by at least on chromosomes 2p14 and 16q12.1, with the possible involve- three independent studies: rs1800629 in the TNF gene, an in- ment of the gene TOX high-mobility group box family mem- sertion/deletion in the ACE gene, and alleles ε2 and ε4 in the ber 3 (TOX3), which plays an important role in the modulation APOE gene(41). The authors concluded that only rs1800629 in of calcium-dependent transcription in neurons, and the non- TNF was significantly associated with the development of ap- coding RNA BC034767. The physiological relationship between nea and could be considered a risk factor for the disease, accord- these new susceptibility loci and the pathogenesis of RLS has ing to published data. yet to be clarified. Overall, functional studies in vitro and in animal models CONCLUSIONS AND FUTURE DIRECTIONS are still needed so that the results from the GWASs can help us Recent scientific and technological advances in the field understand the molecular basis of RLS and be applied in the of human genetics promise to revolutionize the way medicine clinic. is conducted in the future. We can currently move from the expensive curative medicine to an effectively preventive Obstructive sleep apnea/hypopnea syndrome medicine, capable of delaying the onset of diseases and making Obstructive sleep apnea/hypopnea syndrome (OSAHS), longevity available to everyone. The impressive advances in the like other complex phenotypes, is considered a polygenic dis- field of biotechnology are undeniable and definitely irreversible. order with a considerable contribution from environmental Technology and scientific knowledge in the biomedical sciences factors(36,37). Furthermore, it is argued that in the case of OS- has proceeded with unprecedented speed in the last two AHS, intermediate phenotypes, such as variations in craniofa- decades. Initiated in the 1990’s, the Human Genome Project cial morphology, obesity, cardiovascular disease, and respiratory continued for 13 years until the official announcement of its control instability, interact across various dimensions to produce completion in 2003. The entire project had an estimated cost the final phenotype of OSAHS(36). This variety of contribut- of approximately 3 billion dollars, which included funding for ing factors hinders a consistent definition of the phenotype be- the development of previously non-existent laboratory and ing studied, which ultimately influences the outcome of studies computational methods. Today, with the advent of techniques

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