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Annual Review of Genomics and Human Genetics

Volume 25, 2024

The Genetics of Human Sleep and Sleep Disorders

Abstract

Healthy sleep is vital for humans to achieve optimal health and longevity. Poor sleep and sleep disorders are strongly associated with increased morbidity and mortality. However, the importance of good sleep continues to be underrecognized. Mechanisms regulating sleep and its functions in humans remain mostly unclear even after decades of dedicated research. Advancements in gene sequencing techniques and computational methodologies have paved the way for various genetic analysis approaches, which have provided some insights into human sleep genetics. This review summarizes our current knowledge of the genetic basis underlying human sleep traits and sleep disorders. We also highlight the use of animal models to validate genetic findings from human sleep studies and discuss potential molecular mechanisms and signaling pathways involved in the regulation of human sleep.

Keyword(s): circadian rhythms, genome-wide association studies, human sleep genetics, sleep disorders, sleep homeostasis
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/content/journals/10.1146/annurev-genom-121222-120306
2024-08-27
2025-04-25
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Literature Cited

  1. 1.
    Akcimen F, Sarayloo F, Liao C, Ross JP, Oliveira RD, et al. 2020.. Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes. . Commun. Biol. 3::373
     [Crossref] [Google Scholar]
  2. 2.
    Akcimen F, Spiegelman D, Dionne-Laporte A, Gan-Or Z, Dion PA, Rouleau GA. 2018.. Screening of novel restless legs syndrome-associated genes in French-Canadian families. . Neurol. Genet. 4::e296
     [Crossref] [Google Scholar]
  3. 3.
    Al Shareef SM, Basit S, Li S, Pfister C, Pradervand S, et al. 2019.. Kleine-Levin syndrome is associated with LMOD3 variants. . J. Sleep Res. 28::e12849. Correction. 2020.. J. Sleep Res. 29::e12718
     [Google Scholar]
  4. 4.
    Allebrandt KV, Amin N, Müller-Myhsok B, Esko T, Teder-Laving M, et al. 2013.. A KATP channel gene effect on sleep duration: from genome-wide association studies to function in Drosophila. . Mol. Psychiatry 18::122–32
     [Crossref] [Google Scholar]
  5. 5.
    Allebrandt KV, Teder-Laving M, Akyol M, Pichler I, Muller-Myhsok B, et al. 2010.. CLOCK gene variants associate with sleep duration in two independent populations. . Biol. Psychiatry 67::1040–47
     [Crossref] [Google Scholar]
  6. 6.
    Ambati A, Hillary R, Leu-Semenescu S, Ollila HM, Lin L, et al. 2021.. Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci. . PNAS 118::e2005753118
     [Crossref] [Google Scholar]
  7. 7.
    Archer SN, Carpen JD, Gibson M, Lim GH, Johnston JD, et al. 2010.. Polymorphism in the PER3 promoter associates with diurnal preference and delayed sleep phase disorder. . Sleep 33::695–701
     [Crossref] [Google Scholar]
  8. 8.
    Archer SN, Robilliard DL, Skene DJ, Smits M, Williams A, et al. 2003.. A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. . Sleep 26::413–15
     [Crossref] [Google Scholar]
  9. 9.
    Archer SN, Schmidt C, Vandewalle G, Dijk DJ. 2018.. Phenotyping of PER3 variants reveals widespread effects on circadian preference, sleep regulation, and health. . Sleep Med. Rev. 40::109–26
     [Crossref] [Google Scholar]
  10. 10.
    Aridon P, De Fusco M, Winkelmann JW, Zucconi M, Arnao V, et al. 2016.. A TRAPPC6B splicing variant associates to restless legs syndrome. . Parkinsonism Relat. Disord. 31::135–38
     [Crossref] [Google Scholar]
  11. 11.
    Ashbrook LH, Krystal AD, Fu YH, Ptáček LJ. 2020.. Genetics of the human circadian clock and sleep homeostat. . Neuropsychopharmacology 45::45–54
     [Crossref] [Google Scholar]
  12. 12.
    Bachmann V, Klein C, Bodenmann S, Schafer N, Berger W, et al. 2012.. The BDNF Val66Met polymorphism modulates sleep intensity: EEG frequency- and state-specificity. . Sleep 35::335–44
     [Google Scholar]
  13. 13.
    Bassetti CLA, Adamantidis A, Burdakov D, Han F, Gay S, et al. 2019.. Narcolepsy—clinical spectrum, aetiopathophysiology, diagnosis and treatment. . Nat. Rev. Neurol. 15::519–39
     [Crossref] [Google Scholar]
  14. 14.
    Bjorvatn B, Gronli J, Pallesen S. 2010.. Prevalence of different parasomnias in the general population. . Sleep Med. 11::1031–34
     [Crossref] [Google Scholar]
  15. 15.
    Bodenmann S, Hohoff C, Freitag C, Deckert J, Retey JV, et al. 2012.. Polymorphisms of ADORA2A modulate psychomotor vigilance and the effects of caffeine on neurobehavioural performance and sleep EEG after sleep deprivation. . Br. J. Pharmacol. 165::1904–13
     [Crossref] [Google Scholar]
  16. 16.
    Bodenmann S, Landolt HP. 2010.. Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT. . Sleep 33::1027–35
     [Crossref] [Google Scholar]
  17. 17.
    Borbely AA. 1982.. A two process model of sleep regulation. . Hum. Neurobiol. 1::195–204
     [Google Scholar]
  18. 18.
    Brennan KC, Bates EA, Shapiro RE, Zyuzin J, Hallows WC, et al. 2013.. Casein kinase Iδ mutations in familial migraine and advanced sleep phase. . Sci. Transl. Med. 5::183ra56
     [Crossref] [Google Scholar]
  19. 19.
    Cade BE, Gottlieb DJ, Lauderdale DS, Bennett DA, Buchman AS, et al. 2016.. Common variants in DRD2 are associated with sleep duration: the CARe consortium. . Hum. Mol. Genet. 25::167–79
     [Crossref] [Google Scholar]
  20. 20.
    Campos AI, García-Marín LM, Byrne EM, Martin NG, Cuéllar-Partida G, Rentería ME. 2020.. Insights into the aetiology of snoring from observational and genetic investigations in the UK Biobank. . Nat. Commun. 11::817
     [Crossref] [Google Scholar]
  21. 21.
    Campos JHC, Aguilar ACR, Antoneli F, Truzzi G, Briones MRS, et al. 2022.. Whole-genome analysis of monozygotic Brazilian twins discordant for type 1 narcolepsy: a case report. . BMC Neurol. 22::439
     [Crossref] [Google Scholar]
  22. 22.
    Catoire H, Sarayloo F, Amari KM, Apuzzo S, Grant A, et al. 2018.. A direct interaction between two Restless Legs Syndrome predisposing genes: MEIS1 and SKOR1. . Sci. Rep. 8::12173
     [Crossref] [Google Scholar]
  23. 23.
    Chang AM, Bjonnes AC, Aeschbach D, Buxton OM, Gooley JJ, et al. 2016.. Circadian gene variants influence sleep and the sleep electroencephalogram in humans. . Chronobiol. Int. 33::561–73
     [Crossref] [Google Scholar]
  24. 24.
    Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, et al. 1999.. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. . Cell 98::437–51
     [Crossref] [Google Scholar]
  25. 25.
    Chen H, Cade BE, Gleason KJ, Bjonnes AC, Stilp AM, et al. 2018.. Multiethnic meta-analysis identifies RAI1 as a possible obstructive sleep apnea-related quantitative trait locus in men. . Am. J. Respir. Cell Mol. Biol. 58::391–401
     [Crossref] [Google Scholar]
  26. 26.
    Chen S, Francioli LC, Goodrich JK, Collins RL, Kanai M, et al. 2023.. A genomic mutational constraint map using variation in 76,156 human genomes. . Nature 625::92–100
     [Crossref] [Google Scholar]
  27. 27.
    Chen T, Zhang H, Liu Y, Liu YX, Huang L. 2021.. EVenn: easy to create repeatable and editable Venn diagrams and Venn networks online. . J. Genet. Genom. 48::863–66
     [Crossref] [Google Scholar]
  28. 28.
    Dagan Y, Eisenstein M. 1999.. Circadian rhythm sleep disorders: toward a more precise definition and diagnosis. . Chronobiol. Int. 16::213–22
     [Crossref] [Google Scholar]
  29. 29.
    Dashti HS, Daghlas I, Lane JM, Huang Y, Udler MS, et al. 2021.. Genetic determinants of daytime napping and effects on cardiometabolic health. . Nat. Commun. 12::900
     [Crossref] [Google Scholar]
  30. 30.
    Davies B, Brown LA, Cais O, Watson J, Clayton AJ, et al. 2017.. A point mutation in the ion conduction pore of AMPA receptor GRIA3 causes dramatically perturbed sleep patterns as well as intellectual disability. . Hum. Mol. Genet. 26::3869–82
     [Crossref] [Google Scholar]
  31. 31.
    Degn M, Dauvilliers Y, Dreisig K, Lopez R, Pfister C, et al. 2017.. Rare missense mutations in P2RY11 in narcolepsy with cataplexy. . Brain 140::1657–68
     [Crossref] [Google Scholar]
  32. 32.
    Dong Q, Gentry NW, McMahon T, Yamazaki M, Benitez-Rivera L, et al. 2022.. Familial natural short sleep mutations reduce Alzheimer pathology in mice. . iScience 25::103964
     [Crossref] [Google Scholar]
  33. 33.
    Dong Q, Ptáček LJ, Fu YH. 2023.. Mutant β1-adrenergic receptor improves REM sleep and ameliorates tau accumulation in a mouse model of tauopathy. . PNAS 120::e2221686120
     [Crossref] [Google Scholar]
  34. 34.
    Dubowy C, Sehgal A. 2017.. Circadian rhythms and sleep in Drosophila melanogaster. . Genetics 205::1373–97
     [Crossref] [Google Scholar]
  35. 35.
    Ebisawa T, Uchiyama M, Kajimura N, Mishima K, Kamei Y, et al. 2001.. Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome. . EMBO Rep. 2::342–46
     [Crossref] [Google Scholar]
  36. 36.
    Edelson JL, Schneider LD, Amar D, Brink-Kjaer A, Cederberg KL, et al. 2023.. The genetic etiology of periodic limb movement in sleep. . Sleep 46::zsac121
     [Crossref] [Google Scholar]
  37. 37.
    El Gewely M, Welman M, Xiong L, Yin S, Catoire H, et al. 2018.. Reassessing GWAS findings for the shared genetic basis of insomnia and restless legs syndrome. . Sleep 41::zsy164
     [Crossref] [Google Scholar]
  38. 38.
    Fernandez-Santiago R, Iranzo A, Gaig C, Serradell M, Fernandez M, et al. 2017.. MAPT association with REM sleep behavior disorder. . Neurol. Genet. 3::e131
     [Crossref] [Google Scholar]
  39. 39.
    Gallego J. 2012.. Genetic diseases: congenital central hypoventilation, Rett, and Prader-Willi syndromes. . Compr. Physiol. 2::2255–79
     [Crossref] [Google Scholar]
  40. 40.
    Gan-Or Z, Zhou SR, Ambalavanan A, Leblond CS, Xie PX, et al. 2015.. Analysis of functional GLO1 variants in the BTBD9 locus and restless legs syndrome. . Sleep Med. 16::1151–55
     [Crossref] [Google Scholar]
  41. 41.
    Garfield V. 2021.. Sleep duration: a review of genome-wide association studies (GWAS) in adults from 2007 to 2020. . Sleep Med. Rev. 56::101413
     [Crossref] [Google Scholar]
  42. 42.
    Genderson MR, Rana BK, Panizzon MS, Grant MD, Toomey R, et al. 2013.. Genetic and environmental influences on sleep quality in middle-aged men: a twin study. . J. Sleep Res. 22::519–26
     [Crossref] [Google Scholar]
  43. 43.
    Gerstner JR, Perron IJ, Riedy SM, Yoshikawa T, Kadotani H, et al. 2017.. Normal sleep requires the astrocyte brain-type fatty acid binding protein FABP7. . Sci. Adv. 3::e1602663
     [Crossref] [Google Scholar]
  44. 44.
    Goldfarb LG, Petersen RB, Tabaton M, Brown P, Leblanc AC, et al. 1992.. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. . Science 258::806–8
     [Crossref] [Google Scholar]
  45. 45.
    Gottlieb DJ, O'Connor GT, Wilk JB. 2007.. Genome-wide association of sleep and circadian phenotypes. . BMC Med. Genet. 8::S9
     [Crossref] [Google Scholar]
  46. 46.
    Guindalini C, Mazzotti DR, Castro LS, D'Aurea CV, Andersen ML, et al. 2014.. Brain-derived neurotrophic factor gene polymorphism predicts interindividual variation in the sleep electroencephalogram. . J. Neurosci. Res. 92::1018–23
     [Crossref] [Google Scholar]
  47. 47.
    Hale L, Troxel W, Buysse DJ. 2020.. Sleep health: an opportunity for public health to address health equity. . Annu. Rev. Public Health 41::81–99
     [Crossref] [Google Scholar]
  48. 48.
    Hammerschlag AR, Stringer S, de Leeuw CA, Sniekers S, Taskesen E, et al. 2017.. Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits. . Nat. Genet. 49::1584–92
     [Crossref] [Google Scholar]
  49. 49.
    Han F, Lin L, Schormair B, Pizza F, Plazzi G, et al. 2014.. HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency. . Sleep 37::1601–8
     [Crossref] [Google Scholar]
  50. 50.
    Hasan S, van der Veen DR, Winsky-Sommerer R, Hogben A, Laing EE, et al. 2014.. A human sleep homeostasis phenotype in mice expressing a primate-specific PER3 variable-number tandem-repeat coding-region polymorphism. . FASEB J. 28::2441–54
     [Crossref] [Google Scholar]
  51. 51.
    Hasin DS, Sarvet AL, Meyers JL, Saha TD, Ruan WJ, et al. 2018.. Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. . JAMA Psychiatry 75::336–46
     [Crossref] [Google Scholar]
  52. 52.
    He Y, Jones CR, Fujiki N, Xu Y, Guo B, et al. 2009.. The transcriptional repressor DEC2 regulates sleep length in mammals. . Science 325::866–70
     [Crossref] [Google Scholar]
  53. 53.
    Heidbreder A, Frauscher B, Mitterling T, Boentert M, Schirmacher A, et al. 2016.. Not only sleepwalking but NREM parasomnia irrespective of the type is associated with HLA DQB1*05:01. . J. Clin. Sleep Med. 12::565–70
     [Crossref] [Google Scholar]
  54. 54.
    Henrie A, Hemphill SE, Ruiz-Schultz N, Cushman B, DiStefano MT, et al. 2018.. ClinVar Miner: demonstrating utility of a Web-based tool for viewing and filtering ClinVar data. . Hum. Mutat. 39::1051–60
     [Crossref] [Google Scholar]
  55. 55.
    Hida A, Kitamura S, Katayose Y, Kato M, Ono H, et al. 2014.. Screening of clock gene polymorphisms demonstrates association of a PER3 polymorphism with morningness-eveningness preference and circadian rhythm sleep disorder. . Sci. Rep. 4::6309
     [Crossref] [Google Scholar]
  56. 56.
    Hino A, Terada J, Kasai H, Shojima H, Ohgino K, et al. 2020.. Adult cases of late-onset congenital central hypoventilation syndrome and paired-like homeobox 2B-mutation carriers: an additional case report and pooled analysis. . J. Clin. Sleep Med. 16::1891–900
     [Crossref] [Google Scholar]
  57. 57.
    Hirano A, Hsu PK, Zhang LY, Xing LJ, McMahon T, et al. 2018.. DEC2 modulates orexin expression and regulates sleep. . PNAS 115::3434–39
     [Crossref] [Google Scholar]
  58. 58.
    Hirano A, Shi G, Jones CR, Lipzen A, Pennacchio LA, et al. 2016.. A Cryptochrome 2 mutation yields advanced sleep phase in humans. . eLife 5::e16695
     [Crossref] [Google Scholar]
  59. 59.
    Hoang N, Yuen RKC, Howe J, Drmic I, Ambrozewicz P, et al. 2021.. Sleep phenotype of individuals with autism spectrum disorder bearing mutations in the PER2 circadian rhythm gene. . Am. J. Med. Genet. A 185::1120–30
     [Crossref] [Google Scholar]
  60. 60.
    Hohjoh H, Takasu M, Shishikura K, Takahashi Y, Honda Y, Tokunaga K. 2003.. Significant association of the arylalkylamine N-acetyltransferase (AA-NAT) gene with delayed sleep phase syndrome. . Neurogenetics 4::151–53
     [Crossref] [Google Scholar]
  61. 61.
    Hor H, Bartesaghi L, Kutalik Z, Vicario JL, de Andres C, et al. 2011.. A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy. . Am. J. Hum. Genet. 89::474–79
     [Crossref] [Google Scholar]
  62. 62.
    Hu Y, Shmygelska A, Tran D, Eriksson N, Tung JY, Hinds DA. 2016.. GWAS of 89,283 individuals identifies genetic variants associated with self-reporting of being a morning person. . Nat. Commun. 7::10448
     [Crossref] [Google Scholar]
  63. 63.
    Hublin C, Kaprio J. 2003.. Genetic aspects and genetic epidemiology of parasomnias. . Sleep Med. Rev. 7::413–21
     [Crossref] [Google Scholar]
  64. 64.
    Jimenez-Jimenez FJ, Alonso-Navarro H, Garcia-Martin E, Agundez JAG. 2018.. Genetics of restless legs syndrome: an update. . Sleep Med. Rev. 39::108–21
     [Crossref] [Google Scholar]
  65. 65.
    Jones CR, Campbell SS, Zone SE, Cooper F, DeSano A, et al. 1999.. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. . Nat. Med. 5::1062–65
     [Crossref] [Google Scholar]
  66. 66.
    Jones SE, Lane JM, Wood AR, van Hees VT, Tyrrell J, et al. 2019.. Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms. . Nat. Commun. 10::343
     [Crossref] [Google Scholar]
  67. 67.
    Jones SE, Tyrrell J, Wood AR, Beaumont RN, Ruth KS, et al. 2016.. Genome-wide association analyses in 128,266 individuals identifies new morningness and sleep duration loci. . PLOS Genet. 12::e1006125
     [Crossref] [Google Scholar]
  68. 68.
    Khoury S, Wang QP, Parisien M, Gris P, Bortsov AV, et al. 2021.. Multi-ethnic GWAS and meta-analysis of sleep quality identify MPP6 as a novel gene that functions in sleep center neurons. . Sleep 44::zsaa211
     [Crossref] [Google Scholar]
  69. 69.
    Kripke DF, Kline LE, Nievergelt CM, Murray SS, Shadan FF, et al. 2015.. Genetic variants associated with sleep disorders. . Sleep Med. 16::217–24
     [Crossref] [Google Scholar]
  70. 70.
    Kurien P, Hsu PK, Leon J, Wu D, McMahon T, et al. 2019.. TIMELESS mutation alters phase responsiveness and causes advanced sleep phase. . PNAS 116::12045–53
     [Crossref] [Google Scholar]
  71. 71.
    Lane JM, Liang J, Vlasac I, Anderson SG, Bechtold DA, et al. 2017.. Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits. . Nat. Genet. 49::274–81
     [Crossref] [Google Scholar]
  72. 72.
    Lane JM, Qian J, Mignot E, Redline S, Scheer F, Saxena R. 2023.. Genetics of circadian rhythms and sleep in human health and disease. . Nat. Rev. Genet. 24::4–20
     [Crossref] [Google Scholar]
  73. 73.
    Lane JM, Vlasac I, Anderson SG, Kyle SD, Dixon WG, et al. 2016.. Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank. . Nat. Commun. 7::10889
     [Crossref] [Google Scholar]
  74. 74.
    Laposky A, Easton A, Dugovic C, Walisser J, Bradfield C, Turek F. 2005.. Deletion of the mammalian circadian clock gene BMAL1/Mop3 alters baseline sleep architecture and the response to sleep deprivation. . Sleep 28::395–409
     [Crossref] [Google Scholar]
  75. 75.
    Lecendreux M, Bassetti C, Dauvilliers Y, Mayer G, Neidhart E, Tafti M. 2003.. HLA and genetic susceptibility to sleepwalking. . Mol. Psychiatry 8::114–17
     [Crossref] [Google Scholar]
  76. 76.
    Lee DA, Liu J, Hong Y, Lane JM, Hill AJ, et al. 2019.. Evolutionarily conserved regulation of sleep by epidermal growth factor receptor signaling. . Sci. Adv. 5::eaax4249
     [Crossref] [Google Scholar]
  77. 77.
    Liang JJ, Cade BE, He KY, Wang HM, Lee J, et al. 2019.. Sequencing analysis at 8p23 identifies multiple rare variants in DLC1 associated with sleep-related oxyhemoglobin saturation level. . Am. J. Hum. Genet. 105::1057–68
     [Crossref] [Google Scholar]
  78. 78.
    Liang JJ, Wang HM, Cade BE, Kurniansyah N, He KY, et al. 2022.. Targeted genome sequencing identifies multiple rare variants in caveolin-1 associated with obstructive sleep apnea. . Am. J. Respir. Crit. Care Med. 206::1271–80
     [Crossref] [Google Scholar]
  79. 79.
    Liblau RS, Latorre D, Kornum BR, Dauvilliers Y, Mignot EJ. 2023.. The immunopathogenesis of narcolepsy type 1. . Nat. Rev. Immunol. 24::33–48
     [Crossref] [Google Scholar]
  80. 80.
    Licis AK, Desruisseau DM, Yamada KA, Duntley SP, Gurnett CA. 2011.. Novel genetic findings in an extended family pedigree with sleepwalking. . Neurology 76::49–52
     [Crossref] [Google Scholar]
  81. 81.
    Lin L, Faraco J, Li R, Kadotani H, Rogers W, et al. 1999.. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. . Cell 98::365–76
     [Crossref] [Google Scholar]
  82. 82.
    Lind MJ, Gehrman PR. 2016.. Genetic pathways to insomnia. . Brain Sci. 6::64
     [Crossref] [Google Scholar]
  83. 83.
    Lippert J, Halfter H, Heidbreder A, Rohr D, Gess B, et al. 2014.. Altered dynamics in the circadian oscillation of clock genes in dermal fibroblasts of patients suffering from idiopathic hypersomnia. . PLOS ONE 9::e85255
     [Crossref] [Google Scholar]
  84. 84.
    Llorens F, Zarranz JJ, Fischer A, Zerr I, Ferrer I. 2017.. Fatal familial insomnia: clinical aspects and molecular alterations. . Curr. Neurol. Neurosci. Rep. 17::30
     [Crossref] [Google Scholar]
  85. 85.
    Mainieri G, Montini A, Nicotera A, Di Rosa G, Provini F, Loddo G. 2021.. The genetics of sleep disorders in children: a narrative review. . Brain Sci. 11::1259
     [Crossref] [Google Scholar]
  86. 86.
    Manconi M, Garcia-Borreguero D, Schormair B, Videnovic A, Berger K, et al. 2021.. Restless legs syndrome. . Nat. Rev. Dis. Primers 7::80
     [Crossref] [Google Scholar]
  87. 87.
    Maple AM, Rowe RK, Lifshitz J, Fernandez F, Gallitano AL. 2018.. Influence of schizophrenia-associated gene Egr3 on sleep behavior and circadian rhythms in mice. . J. Biol. Rhythms 33::662–70
     [Crossref] [Google Scholar]
  88. 88.
    Masunaga Y, Kagami M, Kato F, Usui T, Yonemoto T, et al. 2021.. Parthenogenetic mosaicism: generation via second polar body retention and unmasking of a likely causative PER2 variant for hypersomnia. . Clin. Epigenet. 13::73
     [Crossref] [Google Scholar]
  89. 89.
    Materna L, Halfter H, Heidbreder A, Boentert M, Lippert J, et al. 2018.. Idiopathic hypersomnia patients revealed longer circadian period length in peripheral skin fibroblasts. . Front. Neurol. 9::424
     [Crossref] [Google Scholar]
  90. 90.
    Mazzotti DR, Guindalini C, de Souza AA, Sato JR, Santos-Silva R, et al. 2012.. Adenosine deaminase polymorphism affects sleep EEG spectral power in a large epidemiological sample. . PLOS ONE 7::e44154
     [Crossref] [Google Scholar]
  91. 91.
    Micic G, Lovato N, Gradisar M, Ferguson SA, Burgess HJ, Lack LC. 2016.. The etiology of delayed sleep phase disorder. . Sleep Med. Rev. 27::29–38
     [Crossref] [Google Scholar]
  92. 92.
    Miyagawa T, Hida A, Shimada M, Uehara C, Nishino Y, et al. 2019.. A missense variant in PER2 is associated with delayed sleep-wake phase disorder in a Japanese population. . J. Hum. Genet. 64::1219–25
     [Crossref] [Google Scholar]
  93. 93.
    Miyagawa T, Tanaka S, Shimada M, Sakai N, Tanida K, et al. 2022.. A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia. . npj Genom. Med. 7::29
     [Crossref] [Google Scholar]
  94. 94.
    Miyagawa T, Tokunaga K. 2019.. Genetics of narcolepsy. . Hum. Genome Var. 6::4
     [Crossref] [Google Scholar]
  95. 95.
    Mogavero MP, DelRosso LM, Bruni O, Salemi M, Salsone M, et al. 2023.. Genetics and epigenetics of rare hypersomnia. . Trends Genet. 39::415–29
     [Crossref] [Google Scholar]
  96. 96.
    Moore H, Winkelmann J, Lin L, Finn L, Peppard P, Mignot E. 2014.. Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD. . Sleep 37::1535–42
     [Crossref] [Google Scholar]
  97. 97.
    Mukherjee S, Saxena R, Palmer LJ. 2018.. The genetics of obstructive sleep apnoea. . Respirology 23::18–27
     [Crossref] [Google Scholar]
  98. 98.
    Narasimamurthy R, Virshup DM. 2021.. The phosphorylation switch that regulates ticking of the circadian clock. . Mol. Cell 81::1133–46
     [Crossref] [Google Scholar]
  99. 99.
    Naylor E, Bergmann BM, Krauski K, Zee PC, Takahashi JS, et al. 2000.. The circadian Clock mutation alters sleep homeostasis in the mouse. . J. Neurosci. 20::8138–43
     [Crossref] [Google Scholar]
  100. 100.
    Pak VM, Mazzotti DR, Keenan BT, Hirotsu C, Gehrman P, et al. 2018.. Candidate gene analysis in the Sao Paulo Epidemiologic Sleep Study (EPISONO) shows an association of variant in PDE4D and sleepiness. . Sleep Med. 47::106–12
     [Crossref] [Google Scholar]
  101. 101.
    Palagini L, Geoffroy PA, Gehrman PR, Miniati M, Gemignani A, Riemann D. 2023.. Potential genetic and epigenetic mechanisms in insomnia: a systematic review. . J. Sleep Res. 32::e13868
     [Crossref] [Google Scholar]
  102. 102.
    Palermo J, Chesi A, Zimmerman A, Sonti S, Pahl MC, et al. 2023.. Variant-to-gene mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as a regulator of sleep. . Sci. Adv. 9::eabq0844
     [Crossref] [Google Scholar]
  103. 103.
    Partinen M, Kaprio J, Koskenvuo M, Putkonen P, Langinvainio H. 1983.. Genetic and environmental determination of human sleep. . Sleep 6::179–85
     [Crossref] [Google Scholar]
  104. 104.
    Patke A, Murphy PJ, Onat OE, Krieger AC, Ozcelik T, et al. 2017.. Mutation of the human circadian clock gene CRY1 in familial delayed sleep phase disorder. . Cell 169::203–15.e13
     [Crossref] [Google Scholar]
  105. 105.
    Pellegrino R, Kavakli IH, Goel N, Cardinale CJ, Dinges DF, et al. 2014.. A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans. . Sleep 37::1327–36
     [Crossref] [Google Scholar]
  106. 106.
    Pereira DS, Tufik S, Louzada FM, Benedito-Silva AA, Lopez AR, et al. 2005.. Association of the length polymorphism in the human Per3 gene with the delayed sleep-phase syndrome: Does latitude have an influence upon it?. Sleep 28::29–32
     [Google Scholar]
  107. 107.
    Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, et al. 2000.. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. . Nat. Med. 6::991–97
     [Crossref] [Google Scholar]
  108. 108.
    Qu WM, Xu XH, Yan MM, Wang YQ, Urade Y, Huang ZL. 2010.. Essential role of dopamine D2 receptor in the maintenance of wakefulness, but not in homeostatic regulation of sleep, in mice. . J. Neurosci. 30::4382–89
     [Crossref] [Google Scholar]
  109. 109.
    Retey JV, Adam M, Honegger E, Khatami R, Luhmann UF, et al. 2005.. A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans. . PNAS 102::15676–81
     [Crossref] [Google Scholar]
  110. 110.
    Rintakoski K, Hublin C, Lobbezoo F, Rose RJ, Kaprio J. 2012.. Genetic factors account for half of the phenotypic variance in liability to sleep-related bruxism in young adults: a nationwide Finnish twin cohort study. . Twin Res. Hum. Genet. 15::714–19
     [Crossref] [Google Scholar]
  111. 111.
    Sateia MJ. 2014.. International classification of sleep disorders-third edition: highlights and modifications. . Chest 146::1387–94
     [Crossref] [Google Scholar]
  112. 112.
    Schenck CH, Boyd JL, Mahowald MW. 1997.. A parasomnia overlap disorder involving sleepwalking, sleep terrors, and REM sleep behavior disorder in 33 polysomnographically confirmed cases. . Sleep 20::972–81
     [Crossref] [Google Scholar]
  113. 113.
    Schenck CH, Garcia-Rill E, Segall M, Noreen H, Mahowald MW. 1996.. HLA class II genes associated with REM sleep behavior disorder. . Ann. Neurol. 39::261–63
     [Crossref] [Google Scholar]
  114. 114.
    Schormair B, Zhao C, Salminen AV, Oexle K, Winkelmann J, Int. EU-RLS-GENE Consort. 2022.. Reassessment of candidate gene studies for idiopathic restless legs syndrome in a large genome-wide association study dataset of European ancestry. . Sleep 45::zsac098
     [Crossref] [Google Scholar]
  115. 115.
    Schrode N, Ho SM, Yamamuro K, Dobbyn A, Huckins L, et al. 2019.. Synergistic effects of common schizophrenia risk variants. . Nat. Genet. 51::1475–85
     [Crossref] [Google Scholar]
  116. 116.
    Sehgal A, Mignot E. 2011.. Genetics of sleep and sleep disorders. . Cell 146::194–207
     [Crossref] [Google Scholar]
  117. 117.
    Shen YC, Sun X, Li L, Zhang HY, Huang ZL, Wang YQ. 2022.. Roles of neuropeptides in sleep-wake regulation. . Int. J. Mol. Sci. 23::4599
     [Crossref] [Google Scholar]
  118. 118.
    Shi GS, Xing LJ, Wu D, Bhattacharyya BJ, Jones CR, et al. 2019.. A rare mutation of β1-adrenergic receptor affects sleep/wake behaviors. . Neuron 103::1044–55
     [Crossref] [Google Scholar]
  119. 119.
    Shi GS, Yin C, Fan ZH, Xing LJ, Mostovoy Y, et al. 2021.. Mutations in metabotropic glutamate receptor 1 contribute to natural short sleep trait. . Curr. Biol. 31::13–24.e4
     [Crossref] [Google Scholar]
  120. 120.
    Sletten TL, Rajaratnam SM, Wright MJ, Zhu G, Naismith S, et al. 2013.. Genetic and environmental contributions to sleep-wake behavior in 12-year-old twins. . Sleep 36::1715–22
     [Crossref] [Google Scholar]
  121. 121.
    Sormann J, Schewe M, Proks P, Jouen-Tachoire T, Rao S, et al. 2022.. Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea. . Nat. Genet. 54::1534–43
     [Crossref] [Google Scholar]
  122. 122.
    Spada J, Sander C, Burkhardt R, Hantzsch M, Mergl R, et al. 2014.. Genetic association of objective sleep phenotypes with a functional polymorphism in the neuropeptide S receptor gene. . PLOS ONE 9::e98789
     [Crossref] [Google Scholar]
  123. 123.
    Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A, et al. 2007.. A genetic risk factor for periodic limb movements in sleep. . New Engl. J. Med. 357::639–47
     [Crossref] [Google Scholar]
  124. 124.
    Strausz T, Strausz S, FinnGen Palotie T, Ahlberg J, Ollila HM. 2023.. Genetic analysis of probable sleep bruxism and its associations with clinical and behavioral traits. . Sleep 46::zsad107
     [Crossref] [Google Scholar]
  125. 125.
    Takahashi JS. 2017.. Transcriptional architecture of the mammalian circadian clock. . Nat. Rev. Genet. 18::164–79
     [Crossref] [Google Scholar]
  126. 126.
    Takano A, Uchiyama M, Kajimura N, Mishima K, Inoue Y, et al. 2004.. A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders. . Neuropsychopharmacology 29::1901–9
     [Crossref] [Google Scholar]
  127. 127.
    Tilch E, Schormair B, Zhao C, Salminen AV, Nikolic AA, et al. 2020.. Identification of restless legs syndrome genes by mutational load analysis. . Ann. Neurol. 87::184–93
     [Crossref] [Google Scholar]
  128. 128.
    Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, et al. 2001.. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. . Science 291::1040–43
     [Crossref] [Google Scholar]
  129. 129.
    Wang H, Cade BE, Chen H, Gleason KJ, Saxena R, et al. 2016.. Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level. . Hum. Mol. Genet. 25::5244–53
     [Google Scholar]
  130. 130.
    Wang H, Lane JM, Jones SE, Dashti HS, Ollila HM, et al. 2019.. Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes. . Nat. Commun. 10::3503
     [Crossref] [Google Scholar]
  131. 131.
    Watanabe K, Jansen PR, Savage JE, Nandakumar P, Wang X, et al. 2022.. Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways. . Nat. Genet. 54::1125–32
     [Crossref] [Google Scholar]
  132. 132.
    Weissbach A, Siegesmund K, Bruggemann N, Schmidt A, Kasten M, et al. 2012.. Exome sequencing in a family with restless legs syndrome. . Mov. Disord. 27::1686–89
     [Crossref] [Google Scholar]
  133. 133.
    Wenz E, Tafti M, Bassetti CLA. 2022.. LMOD3 gene variant in familial periodic hypersomnolence. . Sleep Med. 91::105–8
     [Crossref] [Google Scholar]
  134. 134.
    Wieckiewicz M, Bogunia-Kubik K, Mazur G, Danel D, Smardz J, et al. 2020.. Genetic basis of sleep bruxism and sleep apnea-response to a medical puzzle. . Sci. Rep. 10::7497
     [Crossref] [Google Scholar]
  135. 135.
    Winkelmann J, Lin L, Schormair B, Kornum BR, Faraco J, et al. 2012.. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. . Hum. Mol. Genet. 21::2205–10
     [Crossref] [Google Scholar]
  136. 136.
    Wu T, Hu E, Xu S, Chen M, Guo P, et al. 2021.. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. . Innovation 2::100141
     [Google Scholar]
  137. 137.
    Xing LJ, Shi GS, Mostovoy Y, Gentry NW, Fan ZH, et al. 2019.. Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation. . Sci. Transl. Med. 11::eaax2014
     [Crossref] [Google Scholar]
  138. 138.
    Xu HJ, Liu F, Li ZQ, Li XY, Liu YN, et al. 2022.. Genome-wide association study of obstructive sleep apnea and objective sleep-related traits identifies novel risk loci in Han Chinese individuals. . Am. J. Respir. Crit. Care Med. 206::1534–45
     [Crossref] [Google Scholar]
  139. 139.
    Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, et al. 2005.. Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome. . Nature 434::640–44
     [Crossref] [Google Scholar]
  140. 140.
    Xu Y, Toh KL, Jones CR, Shin JY, Fu YH, Ptáček LJ. 2007.. Modeling of a human circadian mutation yields insights into clock regulation by PER2. . Cell 128::59–70
     [Crossref] [Google Scholar]
  141. 141.
    Yang QB, Li L, Chen QY, Foldvary-Schaefer N, Ondo WG, Wang QK. 2011.. Association studies of variants in MEIS1, BTBD9, and MAP2K5/SKOR1 with restless legs syndrome in a US population. . Sleep Med. 12::800–4
     [Crossref] [Google Scholar]
  142. 142.
    Zaki NFW, Saleh E, Elwasify M, Mahmoud E, Zaki J, et al. 2019.. The association of BDNF gene polymorphism with cognitive impairment in insomnia patients. . Progress Neuro-Psychopharmacol. Biol. Psychiatry 88::253–64
     [Crossref] [Google Scholar]
  143. 143.
    Zhang LY, Hirano A, Hsu PK, Jones CR, Sakai N, et al. 2016.. A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait. . PNAS 113::E1536–44
     [Google Scholar]
  144. 144.
    Zhang MH, Lu Y, Sheng L, Han XX, Yu LM, et al. 2022.. Advances in molecular pathology of obstructive sleep apnea. . Molecules 27::8422
     [Crossref] [Google Scholar]
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The Genetics of Human Sleep and Sleep Disorders
Annual Review of Genomics and Human Genetics 25, 259 (2024); https://doi.org/10.1146/annurev-genom-121222-120306
/content/journals/10.1146/annurev-genom-121222-120306
/content/journals/10.1146/annurev-genom-121222-120306
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