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Genetic Factors in Sleep Disorders: What Are the Roles of Genetic Factors in the Pathogenesis of Sleep Disorders?

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Clinical Relevance of Genetic Factors in Pulmonary Diseases

Abstract

Most normal sleep traits and sleep disorders have a familial aggregation, suggesting significant effects of genetic factors. Obstructive sleep apnea (OSA) is a common and complex sleep disorder and has heritability. A recent genome-wide association study (GWAS) identified some genetic risks for OSA with genome-wide levels of significance for the first time. Congenital central hypoventilation syndrome has causative mutations in the paired-like homeobox 2B (PHOX2B) gene, and its phenotypes are associated with PHOX2B genotypes. GWASs have revealed several genetic variances for restless legs syndrome (RLS), whereas these variances have left most of the heritability in RLS unexplained. Narcolepsy is strongly associated with HLA DQ-B1*06:02, and the results of GWASs indicate an autoimmune pathogenesis of narcolepsy. Insomnia has significant heritability, and findings of GWASs have suggested common genetic predispositions with psychiatric disorders and sleep reactivity. Familial fatal insomnia is an autosomal-dominant genetic disorder caused by a mutation in the prion protein (PRNP) gene. Although advances in genetics have resulted in identification of genetic causes of some sleep disorders, further studies are required to elucidate the cellular and molecular mechanisms from genetic risks to clinical manifestations.

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References

  1. Luyster FS, Strollo PJ Jr, Zee PC, Walsh JK, Boards of Directors of the American Academy of Sleep Medicine and the Sleep Research Society. Sleep: a health imperative. Sleep. 2012;35:727–34.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Alexander M, Ray MA, Hebert JR, Youngstedt SD, Zhang H, Steck SE, et al. The National Veteran Sleep Disorder Study: descriptive epidemiology and secular trends, 2000–2010. Sleep. 2016;39:1399–410.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Parish JM. Genetic and immunologic aspects of sleep and sleep disorders. Chest. 2013;143:1489–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Sateia MJ. International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014;146:1387–94.

    Article  PubMed  Google Scholar 

  5. Gehrman PR, Keenan BT, Byrne EM, Pack AI. Genetics of sleep disorders. Psychiatr Clin North Am. 2015;38:667–81.

    Article  PubMed  Google Scholar 

  6. Andretic R, Franken P, Tafti M. Genetics of sleep. Annu Rev Genet. 2008;42:361–88.

    Article  PubMed  CAS  Google Scholar 

  7. Partinen M, Kaprio J, Koskenvuo M, Putkonen P, Langinvainio H. Genetic and environmental determination of human sleep. Sleep. 1983;6:179–85.

    Article  PubMed  CAS  Google Scholar 

  8. De Gennaro L, Marzano C, Fratello F, Moroni F, Pellicciari MC, Ferlazzo F, et al. The electroencephalographic fingerprint of sleep is genetically determined: a twin study. Ann Neurol. 2008;64:455–60.

    Article  PubMed  Google Scholar 

  9. Nixon GM, Brouillette RT. Sleep and breathing in Prader-Willi syndrome. Pediatr Pulmonol. 2002;34:209–17.

    Article  PubMed  Google Scholar 

  10. Tsuno N, Besset A, Ritchie K. Sleep and depression. J Clin Psychiatry. 2005;66:1254–69.

    Article  PubMed  Google Scholar 

  11. Alcantara C, Biggs ML, Davidson KW, Delaney JA, Jackson CL, Zee PC, et al. Sleep disturbances and depression in the multi-ethnic study of atherosclerosis. Sleep. 2016;39:915–25.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Young T, Palta M, Dempsey J, Peppard PE, Nieto FJ, Hla KM. Burden of sleep apnea: rationale, design, and major findings of the Wisconsin Sleep Cohort study. WMJ. 2009;108:246–9.

    PubMed  PubMed Central  Google Scholar 

  13. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177:1006–14.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Nakayama-Ashida Y, Takegami M, Chin K, Sumi K, Nakamura T, Takahashi K, et al. Sleep-disordered breathing in the usual lifestyle setting as detected with home monitoring in a population of working men in Japan. Sleep. 2008;31:419–25.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chin K, Oga T, Takahashi K, Takegami M, Nakayama-Ashida Y, Wakamura T, et al. Associations between obstructive sleep apnea, metabolic syndrome, and sleep duration, as measured with an actigraph, in an urban male working population in Japan. Sleep. 2010;33:89–95.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Young T, Blustein J, Finn L, Palta M. Sleep-disordered breathing and motor vehicle accidents in a population-based sample of employed adults. Sleep. 1997;20:608–13.

    Article  PubMed  CAS  Google Scholar 

  17. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J. The association between sleep apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander. N Engl J Med. 1999;340:847–51.

    Article  PubMed  CAS  Google Scholar 

  18. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med. 2002;165:1217–39.

    Article  PubMed  Google Scholar 

  19. Quan SF, Wright R, Baldwin CM, Kaemingk KL, Goodwin JL, Kuo TF, et al. Obstructive sleep apnea-hypopnea and neurocognitive functioning in the Sleep Heart Health Study. Sleep Med. 2006;7:498–507.

    Article  PubMed  Google Scholar 

  20. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005;365:1046–53.

    Article  PubMed  Google Scholar 

  21. Yeboah J, Redline S, Johnson C, Tracy R, Ouyang P, Blumenthal RS, et al. Association between sleep apnea, snoring, incident cardiovascular events and all-cause mortality in an adult population: MESA. Atherosclerosis. 2011;219:963–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med. 2001;163:19–25.

    Article  PubMed  CAS  Google Scholar 

  23. Gami AS, Pressman G, Caples SM, Kanagala R, Gard JJ, Davison DE, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation. 2004;110:364–7.

    Article  PubMed  Google Scholar 

  24. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;353:2034–41.

    Article  PubMed  CAS  Google Scholar 

  25. Arnardottir ES, Mackiewicz M, Gislason T, Teff KL, Pack AI. Molecular signatures of obstructive sleep apnea in adults: a review and perspective. Sleep. 2009;32:447–70.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA. 2003;290(14):1906.

    Article  PubMed  CAS  Google Scholar 

  27. Xiong L, Catoire H, Dion P, Gaspar C, Lafreniere RG, Girard SL, et al. MEIS1 intronic risk haplotype associated with restless legs syndrome affects its mRNA and protein expression levels. Hum Mol Genet. 2009;18:1065–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Redline S, Tishler PV. The genetics of sleep apnea. Sleep Med Rev. 2000;4:583–602.

    Article  PubMed  Google Scholar 

  29. Redline S, Tosteson T, Tishler PV, Carskadon MA, Millman RP. Studies in the genetics of obstructive sleep apnea. Familial aggregation of symptoms associated with sleep-related breathing disturbances. Am Rev Respir Dis. 1992;145:440–4.

    Article  PubMed  CAS  Google Scholar 

  30. Redline S, Tishler PV, Tosteson TD, Williamson J, Kump K, Browner I, et al. The familial aggregation of obstructive sleep apnea. Am J Respir Crit Care Med. 1995;151:682–7.

    Article  PubMed  CAS  Google Scholar 

  31. Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet. 1997;27:325–51.

    Article  PubMed  CAS  Google Scholar 

  32. Silventoinen K, Kaprio J. Genetics of tracking of body mass index from birth to late middle age: evidence from twin and family studies. Obes Facts. 2009;2:196–202.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Redline S, Tishler PV, Schluchter M, Aylor J, Clark K, Graham G. Risk factors for sleep-disordered breathing in children. Associations with obesity, race, and respiratory problems. Am J Respir Crit Care Med. 1999;159:1527–32.

    Article  PubMed  CAS  Google Scholar 

  34. Mathur R, Douglas NJ. Family studies in patients with the sleep apnea-hypopnea syndrome. Ann Intern Med. 1995;122:174–8.

    Article  PubMed  CAS  Google Scholar 

  35. Palmer LJ, Buxbaum SG, Larkin EK, Patel SR, Elston RC, Tishler PV, et al. Whole genome scan for obstructive sleep apnea and obesity in African-American families. Am J Respir Crit Care Med. 2004;169:1314–21.

    Article  PubMed  Google Scholar 

  36. Palmer LJ, Buxbaum SG, Larkin E, Patel SR, Elston RC, Tishler PV, et al. A whole-genome scan for obstructive sleep apnea and obesity. Am J Hum Genet. 2003;72:340–50.

    Article  PubMed  CAS  Google Scholar 

  37. Patel SR, Frame JM, Larkin EK, Redline S. Heritability of upper airway dimensions derived using acoustic pharyngometry. Eur Respir J. 2008;32:1304–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. de Paula LK, Alvim RO, Pedrosa RP, Horimoto AR, Krieger JE, Oliveira CM, et al. Heritability of OSA in a rural population. Chest. 2016;149:92–7.

    Article  PubMed  Google Scholar 

  39. Dudley KA, Patel SR. Disparities and genetic risk factors in obstructive sleep apnea. Sleep Med. 2016;18:96–102.

    Article  PubMed  Google Scholar 

  40. Winkelmann J, Schormair B, Xiong L, Dion PA, Rye DB, Rouleau GA. Genetics of restless legs syndrome. Sleep Med. 2017;31:18–22.

    Article  PubMed  Google Scholar 

  41. Cade BE, Chen H, Stilp AM, Gleason KJ, Sofer T, Ancoli-Israel S, et al. Genetic associations with obstructive sleep apnea traits in Hispanic/Latino Americans. Am J Respir Crit Care Med. 2016;194:886–97.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Varvarigou V, Dahabreh IJ, Malhotra A, Kales SN. A review of genetic association studies of obstructive sleep apnea: field synopsis and meta-analysis. Sleep. 2011;34:1461–8.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Xu H, Guan J, Yi H, Yin S. A systematic review and meta-analysis of the association between serotonergic gene polymorphisms and obstructive sleep apnea syndrome. PLoS One. 2014;9:e86460.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Qin B, Sun Z, Liang Y, Yang Z, Zhong R. The association of 5-HT2A, 5-HTT, and LEPR polymorphisms with obstructive sleep apnea syndrome: a systematic review and meta-analysis. PLoS One. 2014;9:e95856.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Sun J, Hu J, Tu C, Zhong A, Xu H. Obstructive sleep apnea susceptibility genes in Chinese population: a field synopsis and meta-analysis of genetic association studies. PLoS One. 2015;10:e0135942.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Lv D, Tan L, Wu Y, Cao C, Deng Z. Leptin and leptin receptor gene polymorphisms in obstructive sleep apnea: a HuGE review and meta-analysis. Sleep Breath. 2015;19:1073–8.

    Article  PubMed  Google Scholar 

  47. Patel SR, Goodloe R, De G, Kowgier M, Weng J, Buxbaum SG, et al. Association of genetic loci with sleep apnea in European Americans and African-Americans: the Candidate Gene Association Resource (CARe). PLoS One. 2012;7:e48836.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Sands-Lincoln M, Grandner M, Whinnery J, Keenan BT, Jackson N, Gurubhagavatula I. The association between obstructive sleep apnea and hypertension by race/ethnicity in a nationally representative sample. J Clin Hypertens (Greenwich). 2013;15:593–9.

    Article  Google Scholar 

  49. Ramos AR, Guilliam D, Dib SI, Koch S. Race/ethnic differences in obstructive sleep apnea risk in patients with acute ischemic strokes in south Florida. Sleep Breath. 2014;18:165–8.

    Article  PubMed  Google Scholar 

  50. Padmanabhan S, Caulfield M, Dominiczak AF. Genetic and molecular aspects of hypertension. Circ Res. 2015;116:937–59.

    Article  PubMed  CAS  Google Scholar 

  51. Lin L, Finn L, Zhang J, Young T, Mignot E. Angiotensin-converting enzyme, sleep-disordered breathing, and hypertension. Am J Respir Crit Care Med. 2004;170:1349–53.

    Article  PubMed  Google Scholar 

  52. Patel SR, Larkin EK, Mignot E, Lin L, Redline S. The association of angiotensin converting enzyme (ACE) polymorphisms with sleep apnea and hypertension. Sleep. 2007;30:531–3.

    Article  PubMed  Google Scholar 

  53. Edwards BA, Eckert DJ, McSharry DG, Sands SA, Desai A, Kehlmann G, et al. Clinical predictors of the respiratory arousal threshold in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2014;190:1293–300.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H, et al. An official ATS clinical policy statement: congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Am J Respir Crit Care Med. 2010;181:626–44.

    Article  PubMed  CAS  Google Scholar 

  55. Ramanantsoa N, Gallego J. Congenital central hypoventilation syndrome. Respir Physiol Neurobiol. 2013;189:272–9.

    Article  PubMed  CAS  Google Scholar 

  56. Moreira TS, Takakura AC, Czeisler C, Otero JJ. Respiratory and autonomic dysfunction in congenital central hypoventilation syndrome. J Neurophysiol. 2016;116:742–52.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  57. Amiel J, Laudier B, Attie-Bitach T, Trang H, de Pontual L, Gener B, et al. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet. 2003;33:459–61.

    Article  PubMed  CAS  Google Scholar 

  58. Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Silvestri JM, Curran ME, et al. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b. Am J Med Genet A. 2003;123A:267–78.

    Article  PubMed  Google Scholar 

  59. Trochet D, O’Brien LM, Gozal D, Trang H, Nordenskjold A, Laudier B, et al. PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome. Am J Hum Genet. 2005;76:421–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Berry-Kravis EM, Zhou L, Rand CM, Weese-Mayer DE. Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype. Am J Respir Crit Care Med. 2006;174:1139–44.

    Article  PubMed  CAS  Google Scholar 

  61. Trochet D, Hong SJ, Lim JK, Brunet JF, Munnich A, Kim KS, et al. Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction. Hum Mol Genet. 2005;14:3697–708.

    Article  PubMed  CAS  Google Scholar 

  62. Matera I, Bachetti T, Puppo F, Di Duca M, Morandi F, Casiraghi GM, et al. PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset Central Hypoventilation syndrome. J Med Genet. 2004;41:373–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Sasaki A, Kanai M, Kijima K, Akaba K, Hashimoto M, Hasegawa H, et al. Molecular analysis of congenital central hypoventilation syndrome. Hum Genet. 2003;114:22–6.

    Article  PubMed  CAS  Google Scholar 

  64. Devriendt K, Fryns JP, Naulaers G, Devlieger H, Alliet P. Neuroblastoma in a mother and congenital central hypoventilation in her daughter: variable expression of the same genetic disorder? Am J Med Genet. 2000;90:430–1.

    Article  PubMed  CAS  Google Scholar 

  65. Weese-Mayer DE, Silvestri JM, Marazita ML, Hoo JJ. Congenital central hypoventilation syndrome: inheritance and relation to sudden infant death syndrome. Am J Med Genet. 1993;47:360–7.

    Article  PubMed  CAS  Google Scholar 

  66. Goridis C, Brunet JF. Central chemoreception: lessons from mouse and human genetics. Respir Physiol Neurobiol. 2010;173:312–21.

    Article  PubMed  CAS  Google Scholar 

  67. Guyenet PG, Mulkey DK. Retrotrapezoid nucleus and parafacial respiratory group. Respir Physiol Neurobiol. 2010;173:244–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Guyenet PG, Stornetta RL, Abbott SB, Depuy SD, Fortuna MG, Kanbar R. Central CO2 chemoreception and integrated neural mechanisms of cardiovascular and respiratory control. J Appl Physiol (1985). 2010;108:995–1002.

    Article  Google Scholar 

  69. Bachetti T, Matera I, Borghini S, Di Duca M, Ravazzolo R, Ceccherini I. Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome. Hum Mol Genet. 2005;14:1815–24.

    Article  PubMed  CAS  Google Scholar 

  70. Wu HT, Su YN, Hung CC, Hsieh WS, Wu KJ. Interaction between PHOX2B and CREBBP mediates synergistic activation: mechanistic implications of PHOX2B mutants. Hum Mutat. 2009;30:655–60.

    Article  PubMed  CAS  Google Scholar 

  71. Ikeda K, Takahashi M, Sato S, Igarashi H, Ishizuka T, Yawo H, et al. A Phox2b BAC transgenic rat line useful for understanding respiratory rhythm generator neural circuitry. PLoS One. 2015;10:e0132475.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Ruffault PL, D’Autreaux F, Hayes JA, Nomaksteinsky M, Autran S, Fujiyama T, et al. The retrotrapezoid nucleus neurons expressing Atoh1 and Phox2b are essential for the respiratory response to CO(2). elife. 2015;4. https://doi.org/10.7554/eLife.07051.

  73. Dubreuil V, Ramanantsoa N, Trochet D, Vaubourg V, Amiel J, Gallego J, et al. A human mutation in Phox2b causes lack of CO2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons. Proc Natl Acad Sci U S A. 2008;105:1067–72.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Ramanantsoa N, Hirsch MR, Thoby-Brisson M, Dubreuil V, Bouvier J, Ruffault PL, et al. Breathing without CO(2) chemosensitivity in conditional Phox2b mutants. J Neurosci. 2011;31:12880–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  75. Garcia Borreguero D, Winkelmann J, Allen RP. Introduction: towards a better understanding of the science of RLS/WED. Sleep Med. 2017;31:1–2.

    Article  PubMed  Google Scholar 

  76. Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, et al. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria—history, rationale, description, and significance. Sleep Med. 2014;15:860–73.

    Article  PubMed  Google Scholar 

  77. Allen RP, Stillman P, Myers AJ. Physician-diagnosed restless legs syndrome in a large sample of primary medical care patients in western Europe: Prevalence and characteristics. Sleep Med. 2010;11:31–7.

    Article  PubMed  Google Scholar 

  78. Allen RP, Bharmal M, Calloway M. Prevalence and disease burden of primary restless legs syndrome: results of a general population survey in the United States. Mov Disord. 2011;26:114–20.

    Article  PubMed  Google Scholar 

  79. Xiong L, Jang K, Montplaisir J, Levchenko A, Thibodeau P, Gaspar C, et al. Canadian restless legs syndrome twin study. Neurology. 2007;68:1631–3.

    Article  PubMed  CAS  Google Scholar 

  80. Lazzarini A, Walters AS, Hickey K, Coccagna G, Lugaresi E, Ehrenberg BL, et al. Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees. Mov Disord. 1999;14:111–6.

    Article  PubMed  CAS  Google Scholar 

  81. Winkelmann J, Muller-Myhsok B, Wittchen HU, Hock B, Prager M, Pfister H, et al. Complex segregation analysis of restless legs syndrome provides evidence for an autosomal dominant mode of inheritance in early age at onset families. Ann Neurol. 2002;52:297–302.

    Article  PubMed  Google Scholar 

  82. Desautels A, Turecki G, Montplaisir J, Sequeira A, Verner A, Rouleau GA. Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q. Am J Hum Genet. 2001;69:1266–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Bonati MT, Ferini-Strambi L, Aridon P, Oldani A, Zucconi M, Casari G. Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain. 2003;126:1485–92.

    Article  PubMed  Google Scholar 

  84. Winkelmann J, Lichtner P, Schormair B, Uhr M, Hauk S, Stiasny-Kolster K, et al. Variants in the neuronal nitric oxide synthase (nNOS, NOS1) gene are associated with restless legs syndrome. Mov Disord. 2008;23:350–8.

    Article  PubMed  Google Scholar 

  85. Schormair B, Kemlink D, Roeske D, Eckstein G, Xiong L, Lichtner P, et al. PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet. 2008;40(8):946.

    Article  PubMed  CAS  Google Scholar 

  86. Mercader N, Leonardo E, Azpiazu N, Serrano A, Morata G, Martinez C, et al. Conserved regulation of proximodistal limb axis development by Meis1/Hth. Nature. 1999;402:425–9.

    Article  PubMed  CAS  Google Scholar 

  87. Dasen JS, Tice BC, Brenner-Morton S, Jessell TM. A Hox regulatory network establishes motor neuron pool identity and target-muscle connectivity. Cell. 2005;123:477–91.

    Article  PubMed  CAS  Google Scholar 

  88. Maeda R, Mood K, Jones TL, Aruga J, Buchberg AM, Daar IO. Xmeis1, a protooncogene involved in specifying neural crest cell fate in Xenopus embryos. Oncogene. 2001;20:1329–42.

    Article  PubMed  CAS  Google Scholar 

  89. Dinev D, Jordan BW, Neufeld B, Lee JD, Lindemann D, Rapp UR, et al. Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells. EMBO Rep. 2001;2:829–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Gross MK, Dottori M, Goulding M. Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord. Neuron. 2002;34:535–49.

    Article  PubMed  CAS  Google Scholar 

  91. Uetani N, Chagnon MJ, Kennedy TE, Iwakura Y, Tremblay ML. Mammalian motoneuron axon targeting requires receptor protein tyrosine phosphatases sigma and delta. J Neurosci. 2006;26:5872–80.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  92. Winkelmann J, Schormair B, Lichtner P, Ripke S, Xiong L, Jalilzadeh S, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet. 2007;39:1000–6.

    Article  PubMed  CAS  Google Scholar 

  93. Winkelmann J, Czamara D, Schormair B, Knauf F, Schulte EC, Trenkwalder C, et al. Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1. PLoS Genet. 2011;7:e1002171.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A, Thorgeirsson TE, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med. 2007;357:639–47.

    Article  PubMed  CAS  Google Scholar 

  95. Earley CJ, Connor J, Garcia-Borreguero D, Jenner P, Winkelman J, Zee PC, et al. Altered brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease). Sleep Med. 2014;15:1288–301.

    Article  PubMed  Google Scholar 

  96. Oexle K, Ried JS, Hicks AA, Tanaka T, Hayward C, Bruegel M, et al. Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels. Hum Mol Genet. 2011;20:1042–7.

    Article  PubMed  CAS  Google Scholar 

  97. Oexle K, Schormair B, Ried JS, Czamara D, Heim K, Frauscher B, et al. Dilution of candidates: the case of iron-related genes in restless legs syndrome. Eur J Hum Genet. 2013;21(4):410.

    Article  PubMed  CAS  Google Scholar 

  98. Moore H IV, Winkelmann J, Lin L, Finn L, Peppard P, Mignot E. Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD. Sleep. 2014;37:1535–42.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Winkelman JW, Blackwell T, Stone K, Ancoli-Israel S, Tranah GJ, Redline S, et al. Genetic associations of periodic limb movements of sleep in the elderly for the MrOS sleep study. Sleep Med. 2015;16:1360–5.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996;273:1516–7.

    Article  PubMed  CAS  Google Scholar 

  101. Schulte EC, Kousi M, Tan PL, Tilch E, Knauf F, Lichtner P, et al. Targeted resequencing and systematic in vivo functional testing identifies rare variants in MEIS1 as significant contributors to restless legs syndrome. Am J Hum Genet. 2014;95:85–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Weissbach A, Siegesmund K, Bruggemann N, Schmidt A, Kasten M, Pichler I, et al. Exome sequencing in a family with restless legs syndrome. Mov Disord. 2012;27:1686–9.

    Article  PubMed  CAS  Google Scholar 

  103. Scammell TE. Narcolepsy. N Engl J Med. 2015;373:2654–62.

    Article  PubMed  CAS  Google Scholar 

  104. Longstreth WT Jr, Koepsell TD, Ton TG, Hendrickson AF, van Belle G. The epidemiology of narcolepsy. Sleep. 2007;30:13–26.

    Article  PubMed  Google Scholar 

  105. Mignot E. Genetic and familial aspects of narcolepsy. Neurology. 1998;50:S16–22.

    Article  PubMed  CAS  Google Scholar 

  106. Mignot E. Sleep, sleep disorders and hypocretin (orexin). Sleep Med. 2004;5(Suppl 1):S2–8.

    Article  PubMed  Google Scholar 

  107. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999;98:437–51.

    Article  PubMed  CAS  Google Scholar 

  108. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27:469–74.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  109. Chabas D, Taheri S, Renier C, Mignot E. The genetics of narcolepsy. Annu Rev Genomics Hum Genet. 2003;4:459–83.

    Article  PubMed  CAS  Google Scholar 

  110. Rogers AE, Meehan J, Guilleminault C, Grumet FC, Mignot E. HLA DR15 (DR2) and DQB1*0602 typing studies in 188 narcoleptic patients with cataplexy. Neurology. 1997;48(6):1550.

    Article  PubMed  CAS  Google Scholar 

  111. Tafti M, Hor H, Dauvilliers Y, Lammers GJ, Overeem S, Mayer G, et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep. 2014;37:19–25.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Pelin Z, Guilleminault C, Risch N, Grumet FC, Mignot E. HLA-DQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups. US Modafinil in Narcolepsy Multicenter Study Group. Tissue Antigens. 1998;51:96–100.

    Article  PubMed  CAS  Google Scholar 

  113. Hong SC, Lin L, Lo B, Jeong JH, Shin YK, Kim SY, et al. DQB1*0301 and DQB1*0601 modulate narcolepsy susceptibility in Koreans. Hum Immunol. 2007;68:59–68.

    Article  PubMed  CAS  Google Scholar 

  114. Ollila HM, Ravel JM, Han F, Faraco J, Lin L, Zheng X, et al. HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am J Hum Genet. 2015;96:136–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Mignot E, Lin L, Rogers W, Honda Y, Qiu X, Lin X, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet. 2001;68:686–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Hallmayer J, Faraco J, Lin L, Hesselson S, Winkelmann J, Kawashima M, et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat Genet. 2009;41:708–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Hor H, Kutalik Z, Dauvilliers Y, Valsesia A, Lammers GJ, Donjacour CE, et al. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat Genet. 2010;42(9):786.

    Article  PubMed  CAS  Google Scholar 

  118. Han F, Faraco J, Dong XS, Ollila HM, Lin L, Li J, et al. Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic. PLoS Genet. 2013;9:e1003880.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Faraco J, Lin L, Kornum BR, Kenny EE, Trynka G, Einen M, et al. ImmunoChip study implicates antigen presentation to T cells in narcolepsy. PLoS Genet. 2013;9:e1003270.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Kornum BR, Kawashima M, Faraco J, Lin L, Rico TJ, Hesselson S, et al. Common variants in P2RY11 are associated with narcolepsy. Nat Genet. 2011;43:66–71.

    Article  PubMed  CAS  Google Scholar 

  121. Miyagawa T, Kawashima M, Nishida N, Ohashi J, Kimura R, Fujimoto A, et al. Variant between CPT1B and CHKB associated with susceptibility to narcolepsy. Nat Genet. 2008;40:1324–8.

    Article  PubMed  CAS  Google Scholar 

  122. Han F, Lin L, Warby SC, Faraco J, Li J, Dong SX, et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol. 2011;70:410–7.

    Article  PubMed  Google Scholar 

  123. Aran A, Lin L, Nevsimalova S, Plazzi G, Hong SC, Weiner K, et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep. 2009;32:979–83.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One. 2012;7:e33536.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Partinen M, Saarenpaa-Heikkila O, Ilveskoski I, Hublin C, Linna M, Olsen P, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One. 2012;7:e33723.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Donadio V, Liguori R, Vandi S, Pizza F, Dauvilliers Y, Leta V, et al. Lower wake resting sympathetic and cardiovascular activities in narcolepsy with cataplexy. Neurology. 2014;83:1080–6.

    Article  PubMed  Google Scholar 

  127. Mignot EJ. A practical guide to the therapy of narcolepsy and hypersomnia syndromes. Neurotherapeutics. 2012;9:739–52.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Mahlios J, De la Herran-Arita AK, Mignot E. The autoimmune basis of narcolepsy. Curr Opin Neurobiol. 2013;23:767–73.

    Article  PubMed  CAS  Google Scholar 

  129. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.

    Book  Google Scholar 

  130. Morin CM. Epidemiology of insomnia. Sleep Med Clin. 2013;8:281–97.

    Article  Google Scholar 

  131. Lind MJ, Gehrman PR. Genetic pathwaysto insomnia. Brain Sci. 2016;6. https://doi.org/10.3390/brainsci6040064.

  132. Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev. 2002;6:97–111.

    Article  PubMed  Google Scholar 

  133. Roth T. Insomnia: definition, prevalence, etiology, and consequences. J Clin Sleep Med. 2007;3:S7–10.

    PubMed  PubMed Central  Google Scholar 

  134. Heath AC, Kendler KS, Eaves LJ, Martin NG. Evidence for genetic influences on sleep disturbance and sleep pattern in twins. Sleep. 1990;13:318–35.

    Article  PubMed  CAS  Google Scholar 

  135. Beaulieu-Bonneau S, LeBlanc M, Merette C, Dauvilliers Y, Morin CM. Family history of insomnia in a population-based sample. Sleep. 2007;30:1739–45.

    Article  PubMed  PubMed Central  Google Scholar 

  136. McCarren M, Goldberg J, Ramakrishnan V, Fabsitz R. Insomnia in Vietnam era veteran twins: influence of genes and combat experience. Sleep. 1994;17:456–61.

    Article  PubMed  CAS  Google Scholar 

  137. Lind MJ, Aggen SH, Kirkpatrick RM, Kendler KS, Amstadter AB. A longitudinal twin study of insomnia symptoms in adults. Sleep. 2015;38:1423–30.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Barclay NL, Gehrman PR, Gregory AM, Eaves LJ, Silberg JL. The heritability of insomnia progression during childhood/adolescence: results from a longitudinal twin study. Sleep. 2015;38:109–18.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Li J, Huang C, Lan Y, Wang Y. A cross-sectional study on the relationships among the polymorphism of period2 gene, work stress, and insomnia. Sleep Breath. 2015;19:1399–406.

    Article  PubMed  Google Scholar 

  140. Brower KJ, Wojnar M, Sliwerska E, Armitage R, Burmeister M. PER3 polymorphism and insomnia severity in alcohol dependence. Sleep. 2012;35:571–7.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Brummett BH, Krystal AD, Ashley-Koch A, Kuhn CM, Zuchner S, Siegler IC, et al. Sleep quality varies as a function of 5-HTTLPR genotype and stress. Psychosom Med. 2007;69:621–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Bouvette-Turcot AA, Pluess M, Bernier A, Pennestri MH, Levitan R, Sokolowski MB, et al. Effects of genotype and sleep on temperament. Pediatrics. 2015;136:e914–21.

    Article  PubMed  Google Scholar 

  143. Harvey CJ, Gehrman P, Espie CA. Who is predisposed to insomnia: a review of familial aggregation, stress-reactivity, personality and coping style. Sleep Med Rev. 2014;18:237–47.

    Article  PubMed  Google Scholar 

  144. Jawinski P, Tegelkamp S, Sander C, Hantzsch M, Huang J, Mauche N, et al. Time to wake up: no impact of COMT Val158Met gene variation on circadian preferences, arousal regulation and sleep. Chronobiol Int. 2016;33:893–905.

    Article  PubMed  CAS  Google Scholar 

  145. Wang CC, Lung FW. The role of PGC-1 and Apoepsilon4 in insomnia. Psychiatr Genet. 2012;22:82–7.

    Article  PubMed  CAS  Google Scholar 

  146. Ziv-Gal A, Flaws JA, Mahoney MM, Miller SR, Zacur HA, Gallicchio L. Genetic polymorphisms in the aryl hydrocarbon receptor-signaling pathway and sleep disturbances in middle-aged women. Sleep Med. 2013;14:883–7.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Ban HJ, Kim SC, Seo J, Kang HB, Choi JK. Genetic and metabolic characterization of insomnia. PLoS One. 2011;6:e18455.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Byrne EM, Gehrman PR, Medland SE, Nyholt DR, Heath AC, Madden PA, et al. A genome-wide association study of sleep habits and insomnia. Am J Med Genet B Neuropsychiatr Genet. 2013;162B:439–51.

    Article  PubMed  CAS  Google Scholar 

  149. Parsons MJ, Lester KJ, Barclay NL, Nolan PM, Eley TC, Gregory AM. Replication of Genome-Wide Association Studies (GWAS) loci for sleep in the British G1219 cohort. Am J Med Genet B Neuropsychiatr Genet. 2013;162B:431–8.

    Article  PubMed  CAS  Google Scholar 

  150. Spada J, Scholz M, Kirsten H, Hensch T, Horn K, Jawinski P, et al. Genome-wide association analysis of actigraphic sleep phenotypes in the LIFE Adult Study. J Sleep Res. 2016;25:690–701.

    Article  PubMed  Google Scholar 

  151. Amin N, Allebrandt KV, van der Spek A, Muller-Myhsok B, Hek K, Teder-Laving M, et al. Genetic variants in RBFOX3 are associated with sleep latency. Eur J Hum Genet. 2016;24:1488–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Gressier F, Calati R, Balestri M, Marsano A, Alberti S, Antypa N, et al. The 5-HTTLPR polymorphism and posttraumatic stress disorder: a meta-analysis. J Trauma Stress. 2013;26:645–53.

    Article  PubMed  Google Scholar 

  153. Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, et al. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA. 2009;301:2462–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. van der Werf YD, Altena E, van Dijk KD, Strijers RL, De Rijke W, Stam CJ, et al. Is disturbed intracortical excitability a stable trait of chronic insomnia? A study using transcranial magnetic stimulation before and after multimodal sleep therapy. Biol Psychiatry. 2010;68:950–5.

    Article  PubMed  Google Scholar 

  155. Buysse DJ, Germain A, Hall M, Monk TH, Nofzinger EA. A neurobiological model of insomnia. Drug Discov Today Dis Models. 2011;8:129–37.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Drake CL, Friedman NP, Wright KP Jr, Roth T. Sleep reactivity and insomnia: genetic and environmental influences. Sleep. 2011;34:1179–88.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Kalmbach DA, Pillai V, Arnedt JT, Drake CL. Identifying at-risk individuals for insomnia using the Ford insomnia response to stress test. Sleep. 2016;39:449–56.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Llorens F, Zarranz JJ, Fischer A, Zerr I, Ferrer I. Fatal familial insomnia: clinical aspects and molecular alterations. Curr Neurol Neurosci Rep. 2017;17:30.

    Article  PubMed  CAS  Google Scholar 

  159. Medori R, Tritschler HJ, LeBlanc A, Villare F, Manetto V, Chen HY, et al. Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N Engl J Med. 1992;326:444–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  160. Medori R, Montagna P, Tritschler HJ, LeBlanc A, Cortelli P, Tinuper P, et al. Fatal familial insomnia: a second kindred with mutation of prion protein gene at codon 178. Neurology. 1992;42:669–70.

    Article  PubMed  CAS  Google Scholar 

  161. Goldfarb LG, Petersen RB, Tabaton M, Brown P, LeBlanc AC, Montagna P, et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science. 1992;258:806–8.

    Article  PubMed  CAS  Google Scholar 

  162. Krasnianski A, Bartl M, Sanchez Juan PJ, Heinemann U, Meissner B, Varges D, et al. Fatal familial insomnia: clinical features and early identification. Ann Neurol. 2008;63:658–61.

    Article  PubMed  Google Scholar 

  163. Krasnianski A, Heinemann U, Ponto C, Kortt J, Kallenberg K, Varges D, et al. Clinical findings and diagnosis in genetic prion diseases in Germany. Eur J Epidemiol. 2016;31:187–96.

    Article  PubMed  CAS  Google Scholar 

  164. Montagna P, Gambetti P, Cortelli P, Lugaresi E. Familial and sporadic fatal insomnia. Lancet Neurol. 2003;2:167–76.

    Article  PubMed  CAS  Google Scholar 

  165. Cortelli P, Fabbri M, Calandra-Buonaura G, Capellari S, Tinuper P, Parchi P, et al. Gait disorders in fatal familial insomnia. Mov Disord. 2014;29:420–4.

    Article  PubMed  Google Scholar 

  166. Pedroso JL, Pinto WB, Souza PV, Ricarte IF, Landemberger MC, Martins VR, et al. Complex movement disorders in fatal familial insomnia: a clinical and genetic discussion. Neurology. 2013;81:1098–9.

    Article  PubMed  Google Scholar 

  167. Montagna P, Cortelli P, Avoni P, Tinuper P, Plazzi G, Gallassi R, et al. Clinical features of fatal familial insomnia: phenotypic variability in relation to a polymorphism at codon 129 of the prion protein gene. Brain Pathol. 1998;8:515–20.

    Article  PubMed  CAS  Google Scholar 

  168. Gambetti P, Lugaresi E. Conclusions of the symposium. Brain Pathol. 1998;8:571–5.

    Article  PubMed  CAS  Google Scholar 

  169. Gambetti P, Parchi P, Petersen RB, Chen SG, Lugaresi E. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: clinical, pathological and molecular features. Brain Pathol. 1995;5:43–51.

    Article  PubMed  CAS  Google Scholar 

  170. Dimitri D, Jehel L, Durr A, Levy-Soussan M, Andreux V, Laplanche JL, et al. Fatal familial insomnia presenting as psychosis in an 18-year-old man. Neurology. 2006;67:363–4.

    Article  PubMed  CAS  Google Scholar 

  171. Parchi P, Castellani R, Cortelli P, Montagna P, Chen SG, Petersen RB, et al. Regional distribution of protease-resistant prion protein in fatal familial insomnia. Ann Neurol. 1995;38:21–9.

    Article  PubMed  CAS  Google Scholar 

  172. Parchi P, Petersen RB, Chen SG, Autilio-Gambetti L, Capellari S, Monari L, et al. Molecular pathology of fatal familial insomnia. Brain Pathol. 1998;8:539–48.

    Article  PubMed  CAS  Google Scholar 

  173. Capellari S, Strammiello R, Saverioni D, Kretzschmar H, Parchi P. Genetic Creutzfeldt-Jakob disease and fatal familial insomnia: insights into phenotypic variability and disease pathogenesis. Acta Neuropathol. 2011;121:21–37.

    Article  PubMed  CAS  Google Scholar 

  174. Krasnianski A, Sanchez Juan P, Ponto C, Bartl M, Heinemann U, Varges D, et al. A proposal of new diagnostic pathway for fatal familial insomnia. J Neurol Neurosurg Psychiatry. 2014;85:654–9.

    Article  PubMed  CAS  Google Scholar 

  175. Lee S, Antony L, Hartmann R, Knaus KJ, Surewicz K, Surewicz WK, et al. Conformational diversity in prion protein variants influences intermolecular beta-sheet formation. EMBO J. 2010;29:251–62.

    Article  PubMed  CAS  Google Scholar 

  176. Riek R, Wider G, Billeter M, Hornemann S, Glockshuber R, Wuthrich K. Prion protein NMR structure and familial human spongiform encephalopathies. Proc Natl Acad Sci U S A. 1998;95:11667–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Swietnicki W, Petersen RB, Gambetti P, Surewicz WK. Familial mutations and the thermodynamic stability of the recombinant human prion protein. J Biol Chem. 1998;273:31048–52.

    Article  PubMed  CAS  Google Scholar 

  178. Tian C, Liu D, Sun QL, Chen C, Xu Y, Wang H, et al. Comparative analysis of gene expression profiles between cortex and thalamus in Chinese fatal familial insomnia patients. Mol Neurobiol. 2013;48:36–48.

    Article  PubMed  CAS  Google Scholar 

  179. Frau-Mendez MA, Fernandez-Vega I, Ansoleaga B, Blanco Tech R, Carmona Tech M, Antonio Del Rio J, et al. Fatal familial insomnia: mitochondrial and protein synthesis machinery decline in the mediodorsal thalamus. Brain Pathol. 2017;27:95–106.

    Article  PubMed  CAS  Google Scholar 

  180. Panda S. Circadian physiology of metabolism. Science. 2016;354:1008–15.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  181. Jones CR, Campbell SS, Zone SE, Cooper F, DeSano A, Murphy PJ, et al. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat Med. 1999;5:1062–5.

    Article  PubMed  CAS  Google Scholar 

  182. Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science. 2001;291:1040–3.

    Article  PubMed  CAS  Google Scholar 

  183. Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, et al. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature. 2005;434:640–4.

    Article  PubMed  CAS  Google Scholar 

  184. Vink JM, Groot AS, Kerkhof GA, Boomsma DI. Genetic analysis of morningness and eveningness. Chronobiol Int. 2001;18:809–22.

    Article  PubMed  CAS  Google Scholar 

  185. Aguiar GF, da Silva HP, Marques N. Patterns of daily allocation of sleep periods: a case study in an Amazonian riverine community. Chronobiologia. 1991;18:9–19.

    PubMed  CAS  Google Scholar 

  186. Carpen JD, Archer SN, Skene DJ, Smits M, von Schantz M. A single-nucleotide polymorphism in the 5′-untranslated region of the hPER2 gene is associated with diurnal preference. J Sleep Res. 2005;14:293–7.

    Article  PubMed  Google Scholar 

  187. Carpen JD, von Schantz M, Smits M, Skene DJ, Archer SN. A silent polymorphism in the PER1 gene associates with extreme diurnal preference in humans. J Hum Genet. 2006;51:1122–5.

    Article  PubMed  CAS  Google Scholar 

  188. Katzenberg D, Young T, Finn L, Lin L, King DP, Takahashi JS, et al. A CLOCK polymorphism associated with human diurnal preference. Sleep. 1998;21:569–76.

    Article  PubMed  CAS  Google Scholar 

  189. Mishima K, Tozawa T, Satoh K, Saitoh H, Mishima Y. The 3111T/C polymorphism of hClock is associated with evening preference and delayed sleep timing in a Japanese population sample. Am J Med Genet B Neuropsychiatr Genet. 2005;133B:101–4.

    Article  PubMed  Google Scholar 

  190. Parsons MJ, Lester KJ, Barclay NL, Archer SN, Nolan PM, Eley TC, et al. Polymorphisms in the circadian expressed genes PER3 and ARNTL2 are associated with diurnal preference and GNbeta3 with sleep measures. J Sleep Res. 2014;23:595–604.

    Article  PubMed  PubMed Central  Google Scholar 

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  1. Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kiminobu Tanizawa & Kazuo Chin

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    Takeshi Kaneko

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Tanizawa, K., Chin, K. (2018). Genetic Factors in Sleep Disorders: What Are the Roles of Genetic Factors in the Pathogenesis of Sleep Disorders?. In: Kaneko, T. (eds) Clinical Relevance of Genetic Factors in Pulmonary Diseases. Respiratory Disease Series: Diagnostic Tools and Disease Managements. Springer, Singapore. https://doi.org/10.1007/978-981-10-8144-6_13

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