Sleep and Biological Rhythms

, Volume 14, Issue 1, pp 55–62 | Cite as

Circadian clock gene variants and insomnia, sleepiness, and shift work disorder

  • Eirunn Thun
  • S. Le Hellard
  • T. M. Osland
  • B. Bjorvatn
  • B. E. Moen
  • N. Magerøy
  • V. M. Steen
  • S. Giddaluru
  • H.-R. Brattbakk
  • S. Pallesen
Original Article


Shift workers often experience circadian misalignment and problems adjusting adequately to their work schedules, which is manifested in the high prevalence rates of shift work disorder, insomnia and sleepiness in this group of workers compared to day workers. However, there exist large inter-individual differences in tolerance to shift work. We investigated whether frequency variation in single nucleotide polymorphisms capturing genetic variation in genes involved in the regulation of circadian rhythms (clock genes) was associated with insomnia, sleepiness, and shift work disorder in a sample of Norwegian nurses employed in various work schedules. Saliva samples from 691 female nurses participating in “the Survey on Shift work, Sleep and Health” were analysed for associations between genetic variations in clock genes and the nurses’ survey responses. A total of 662 single nucleotide polymorphisms were analysed. After multiple testing correction, we did not observe any statistically significant associations between the genetic variants and insomnia, sleepiness, or shift work disorder.


Clock genes Single nucleotide polymorphisms Insomnia Sleepiness Shift work disorder 



We acknowledge the technical support and service from the Genomics Core Facility (GCF) at the Department of Clinical Science, the University of Bergen. The “SUSSH” study received a grant from The Western Norway Regional Health Authority (no personal payment/salary). Expenses related to mailing of questionnaires were covered by The Norwegian Nurses Organization (no personal payment/salary).

Supplementary material

41105_2015_23_MOESM1_ESM.xlsx (150 kb)
Supplementary material 1 (XLSX 150 kb)


  1. 1.
    Kriegsfeld L, Silver R. The regulation of neuroendocrine function: timing is everything. Horm Behav. 2006;49:557–74.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Annu Rev Neurosci. 2012;35:445–62.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Albrecht U. Invited review: regulation of mammalian circadian clock genes. J Appl Physiol. 2002;92:1348–55.CrossRefPubMedGoogle Scholar
  4. 4.
    Czeisler C, Duffy J, Shanahan T, Brown E, Mitchell J, Rimmer D, Ronda JM, Silva EJ, Allan JS, Emens JS, Dijk D-J, Kronauer RE. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science. 1999;284:2177–81.CrossRefPubMedGoogle Scholar
  5. 5.
    Reppert S. Cellular and molecular basis of circadian timing in mammals. Semin Perinatol. 2000;24:243–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Waterhouse J, Reilly T, Atkinson G, Edwards B. Jet lag: trends and coping strategies. Lancet. 2007;369:1117–29.CrossRefPubMedGoogle Scholar
  7. 7.
    Haus E, Smolensky M. Biological clocks and shift work: circadian dysregulation and potential long-term effects. Cancer Causes Control. 2006;17:489–500.CrossRefPubMedGoogle Scholar
  8. 8.
    Folkard S. Do permanent night workers show circadian adjustment? A review based on the endogenous melatonin rhythm. Chronobiol Int. 2008;25:215–24.CrossRefPubMedGoogle Scholar
  9. 9.
    Eldevik MF, Flo E, Moen BE, Pallesen S, Bjorvatn B. Insomnia, excessive sleepiness, excessive fatigue, anxiety, depression and shift work disorder in nurses having less than 11 hours in-between shifts. PLoS One. 2013;8:e70882.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Drake CL, Roehrs T, Richardson G, Walsh JK, Roth T. Shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep. 2004;27:1453–62.PubMedGoogle Scholar
  11. 11.
    Ohayon MM, Lemoine P, Arnaud-Briant V, Dreyfus M. Prevalence and consequences of sleep disorders in a shift worker population. J Psychosom Res. 2002;53:577–83.CrossRefPubMedGoogle Scholar
  12. 12.
    Lazar AS, Slak A, Lo JC, Santhi N, von Schantz M, Archer SN, Groeger JA, Dijk DJ. Sleep, diurnal preference, health, and psychological well-being: a prospective single-allelic-variation study. Chronobiol Int. 2012;29:131–46.CrossRefPubMedGoogle Scholar
  13. 13.
    Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001;2:297–307.CrossRefPubMedGoogle Scholar
  14. 14.
    Johns M. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14:540–5.PubMedGoogle Scholar
  15. 15.
    Gamble KL, Motsinger-Reif AA, Hida A, Borsetti HM, Servick SV, Ciarleglio CM, Robbins S, Hicks J, Carver K, Hamilton N, Wells N, Summar ML, McMahon DG, Johnson CH. Shift work in nurses: contribution of phenotypes and genotypes to adaptation. PLoS One. 2011;6:e18395.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Serretti A, Benedetti F, Mandelli L, Lorenzi C, Pirovano A, Colombo C, Smeraldi E. Genetic dissection of psychopathological symptoms: insomnia in mood disorders and clock gene polymorphism. Am J Med Genet B. 2003;121B:35–8.CrossRefGoogle Scholar
  17. 17.
    Serretti A, Cusin C, Benedetti F, Mandelli L, Pirovano A, Zanardi R, Colombo C, Smeraldi E. Insomnia improvement during antidepressant treatment and CLOCK gene polymorphism. Am J Med Genet B Neuropsychiatr Genet. 2005;137B:36–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Lattuada E, Cavallaro R, Benedetti F, Cocchi F, Lorenzi C, Smeraldi E. Genetic dissection of drug effects in clinical practice: CLOCK gene and clozapine-induced diurnal sleepiness. Neurosci Lett. 2004;367:152–5.CrossRefPubMedGoogle Scholar
  19. 19.
    Serretti A, Gaspar-Barba E, Calati R, Cruz-Fuentes C, Gomez-Sanchez A, Perez-Molina A, De Ronchi D. 3111 T/C CLOCK gene polymorphism is not associated with sleep disturbances in untreated depressed patients. Chronobiol Int. 2010;27:265–77.CrossRefPubMedGoogle Scholar
  20. 20.
    Flo E, Pallesen S, Akerstedt T, Mageroy N, Moen BE, Gronli J, Nordhus IH, Bjorvatn B. Shift-related sleep problems vary according to work schedule. Occup Environ Med. 2013;70:238–45.CrossRefPubMedGoogle Scholar
  21. 21.
    Reknes I, Pallesen S, Mageroy N, Moen BE, Bjorvatn B, Einarsen S. Exposure to bullying behaviors as a predictor of mental health problems among Norwegian nurses: results from the prospective SUSSH-survey. Int J Nurs Stud. 2014;51:479–87.CrossRefPubMedGoogle Scholar
  22. 22.
    Roelen CA, Mageroy N, van Rhenen W, Groothoff JW, van der Klink JJ, Pallesen S, Bjorvatn B, Moen BE. Low job satisfaction does not identify nurses at risk of future sickness absence: results from a Norwegian cohort study. Int J Nurs Stud. 2013;50:366–73.CrossRefPubMedGoogle Scholar
  23. 23.
    Saksvik-Lehouillier I, Bjorvatn B, Hetland H, Sandal GM, Moen BE, Magerøy N, Harvey A, Costa G, Pallesen S. Personality factors predicting changes in shift work tolerance: a longitudinal study among nurses working rotating shifts. Work Stress. 2012;26:143–60.CrossRefGoogle Scholar
  24. 24.
    Thun E, Bjorvatn B, Torsheim T, Moen BE, Mageroy N, Pallesen S. Night work and symptoms of anxiety and depression among nurses: a longitudinal study. Work Stress. 2014;28:376–86.CrossRefGoogle Scholar
  25. 25.
    Vedaa Ø, Bjorvatn B, Magerøy N, Thun E, Pallesen S. Longitudinal predictors of changes in the morningness–eveningness personality among Norwegian nurses. Pers Indiv Differ. 2013;55:152–6.CrossRefGoogle Scholar
  26. 26.
    Pallesen S, Bjorvatn B, Nordhus I, Sivertsen B, Hjørnevik M, Morin C. A new scale for measuring insomnia: the Bergen Insomnia Scale. Percept Mot Skills. 2008;107:691–706.PubMedGoogle Scholar
  27. 27.
    American Academy of Sleep Medicine. The International Classification of Sleep Disorders: Diagnostic and Coding Manual. 2nd ed. Westchester: American Academy of Sleep Medicine; 2005.Google Scholar
  28. 28.
    Flo E, Pallesen S, Mageroy N, Moen BE, Gronli J, Nordhus IH, Bjorvatn B. Shift work disorder in nurses–assessment, prevalence and related health problems. PLoS One. 2012;7:e33981.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Waage S, Moen BE, Pallesen S, Eriksen HR, Ursin H, Akerstedt T, Bjorvatn B. Shift work disorder among oil rig workers in the north sea. Sleep. 2009;32:558–65.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Christoforou A, Dondrup M, Mattingsdal M, Mattheisen M, Giddaluru S, Nothen MM, Rietschel M, Cichon S, Djurovic S, Andreassen OA, Jonassen I, Steen VM, Puntervoll P, Le Hellard S. Linkage-disequilibrium-based binning affects the interpretation of GWASs. Am J Hum Genet. 2012;90:727–33.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Kripke DF, Nievergelt CM, Joo E, Shekhtman T, Kelsoe JR. Circadian polymorphisms associated with affective disorders. J Circadian Rhythms. 2009;7:2.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Lavebratt C, Sjöholm L, Partonen T, Schalling M, Forsell Y. PER2 variantion is associated with depression vulnerability. Am J Med Genet B Neuropsychiatr Genet. 2009;153B:570–81.Google Scholar
  33. 33.
    Soria V, Martinez-Amoros E, Escaramis G, Valero J, Perez-Egea R, Garcia C, Gutierrez-Zotes A, Puigdemont D, Bayes M, Crespo JM, Martorell L, Vilella E, Labad A, Vallejo J, Perez V, Menchon JM, Estivill X, Gratacos M, Urretavizcaya M. Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder. Neuropsychopharmacology. 2010;35:1279–89.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Nievergelt CM, Kripke DF, Barrett TB, Burg E, Remick RA, Sadovnick AD, McElroy SL, Keck PE Jr, Schork NJ, Kelsoe JR. Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:234–41.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Pickard BS, Christoforou A, Thomson PA, Fawkes A, Evans KL, Morris SW, Porteous DJ, Blackwood DH, Muir WJ. Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder. Mol Psychiatry. 2009;14:874–84.CrossRefPubMedGoogle Scholar
  36. 36.
    Akashi M, Takumi T. The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1. Nat Struct Mol Biol. 2005;12:441–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Watson NF, Goldberg J, Arguelles L, Buchwald D. Genetic and environmental influences on insomnia, daytime sleepiness, and obesity in twins. Sleep. 2006;29:645–9.PubMedGoogle Scholar
  38. 38.
    Byrne EM, Gehrman PR, Medland SE, Nyholt DR, Heath AC, Madden PA, Hickie IB, Van Duijn CM, Henders AK, Montgomery GW, Martin NG, Wray NR, Chronogen C. A genome-wide association study of sleep habits and insomnia. Am J Med Genet B Neuropsychiatr Genet. 2013;162B:439–51.CrossRefPubMedGoogle Scholar
  39. 39.
    Le Hellard S, Steen VM. Genetic architecture of cognitive traits. Scand J Psychol. 2014;55:255–62.CrossRefPubMedGoogle Scholar
  40. 40.
    Knutsson A. Methodological aspects of shift-work research. Chronobiol Int. 2004;21:1037–47.CrossRefPubMedGoogle Scholar
  41. 41.
    Asaoka S, Aritake S, Komada Y, Ozaki A, Odagiri Y, Inoue S, Shimomitsu T, Inoue Y. Factors associated with shift work disorder in nurses working with rapid-rotation schedules in Japan: the nurses’ sleep health project. Chronobiol Int. 2013;30:628–36.CrossRefPubMedGoogle Scholar
  42. 42.
    Krystal AD, Edinger J, Wohlgemuth W, Marsh GR. Sleep in peri-menopausal and post-menopausal women. Sleep Med Rev. 1998;2:243–53.CrossRefPubMedGoogle Scholar
  43. 43.
    Faraco J, Mignot E. Genetics of sleep and sleep disorders in humans. In: Kryger M, Roth T, Dement W, editors. Principles and practice of sleep medicine. 5th ed. St. Louis: Elsevier Saunders; 2011. p. 184–98.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Sleep Research 2015

Authors and Affiliations

  • Eirunn Thun
    • 1
  • S. Le Hellard
    • 2
    • 3
  • T. M. Osland
    • 2
    • 3
  • B. Bjorvatn
    • 4
    • 5
  • B. E. Moen
    • 6
  • N. Magerøy
    • 7
  • V. M. Steen
    • 2
    • 3
  • S. Giddaluru
    • 2
    • 3
  • H.-R. Brattbakk
    • 2
    • 3
  • S. Pallesen
    • 1
    • 4
  1. 1.Department of Psychosocial ScienceUniversity of BergenBergenNorway
  2. 2.Department of Clinical ScienceKG Jebsen Centre for Psychosis Research, The Norwegian Centre for Mental Disorders Research (NORMENT), University of BergenBergenNorway
  3. 3.Dr. Einar Martens Research Group for Biological PsychiatryCenter for Medical Genetics and Molecular Medicine, Haukeland University HospitalBergenNorway
  4. 4.Norwegian Competence Center for Sleep Disorders, Haukeland University HospitalBergenNorway
  5. 5.Department of Global Public Health and Primary CareUniversity of BergenBergenNorway
  6. 6.Centre for International HealthUniversity of BergenBergenNorway
  7. 7.Department of Occupational MedicineHaukeland University HospitalBergenNorway

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