Genomics & Informatics

Korea Genome Organization (한국유전체학회)
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Investigation of gene-gene interactions of clock genes for chronotype in a healthy Korean population

  • Park, Mira (Department of Preventive Medicine, Eulji University School of Medicine) ;
  • Kim, Soon Ae (Department of Pharmacology, Eulji University School of Medicine) ;
  • Shin, Jieun (Department of Liberal Arts, Woosuk University) ;
  • Joo, Eun-Jeong (Department of Neuropsychiatry, Eulji University School of Medicine)
  • Received : 2020.10.06
  • Accepted : 2020.11.07
  • Published : 2020.12.31
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Abstract

Chronotype is an important moderator of psychiatric illnesses, which seems to be controlled in some part by genetic factors. Clock genes are the most relevant genes for chronotype. In addition to the roles of individual genes, gene-gene interactions of clock genes substantially contribute to chronotype. We investigated genetic associations and gene-gene interactions of the clock genes BHLHB2, CLOCK, CSNK1E, NR1D1, PER1, PER2, PER3, and TIMELESS for chronotype in 1,293 healthy Korean individuals. Regression analysis was conducted to find associations between single nucleotide polymorphism (SNP) and chronotype. For gene-gene interaction analyses, the quantitative multifactor dimensionality reduction (QMDR) method, a nonparametric model-free method for quantitative phenotypes, were performed. No individual SNP or haplotype showed a significant association with chronotype by both regression analysis and single-locus model of QMDR. QMDR analysis identified NR1D1 rs2314339 and TIMELESS rs4630333 as the best SNP pairs among two-locus interaction models associated with chronotype (cross-validation consistency [CVC] = 8/10, p = 0.041). For the three-locus interaction model, the SNP combination of NR1D1 rs2314339, TIMELESS rs4630333, and PER3 rs228669 showed the best results (CVC = 4/10, p < 0.001). However, because the mean differences between genotype combinations were minor, the clinical roles of clock gene interactions are unlikely to be critical.

Keywords

Acknowledgement

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) & funded by the Korean government (MSIP&MOHW) (No. 2016M3A9B6904241, 2016M3A9B6904244).

References

  1. Roenneberg T, Merrow M. Entrainment of the human circadian clock. Cold Spring Harb Symp Quant Biol 2007;72:293-299. https://doi.org/10.1101/sqb.2007.72.043
  2. Duffy JF, Czeisler CA. Age-related change in the relationship between circadian period, circadian phase, and diurnal preference in humans. Neurosci Lett 2002;318:117-120. https://doi.org/10.1016/S0304-3940(01)02427-2
  3. Allebrandt KV, Teder-Laving M, Kantermann T, Peters A, Campbell H, Rudan I, et al. Chronotype and sleep duration: the influence of season of assessment. Chronobiol Int 2014;31:731-740. https://doi.org/10.3109/07420528.2014.901347
  4. Fischer D, Lombardi DA, Marucci-Wellman H, Roenneberg T. Chronotypes in the US: influence of age and sex. PLoS One 2017;12:e0178782. https://doi.org/10.1371/journal.pone.0178782
  5. Horne JA, Ostberg O. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol 1976;4:97-110.
  6. Smith CS, Reilly C, Midkiff K. Evaluation of three circadian rhythm questionnaires with suggestions for an improved measure of morningness. J Appl Psychol 1989;74:728-738. https://doi.org/10.1037/0021-9010.74.5.728
  7. Barclay NL, Eley TC, Buysse DJ, Archer SN, Gregory AM. Diurnal preference and sleep quality: same genes? A study of young adult twins. Chronobiol Int 2010;27:278-296. https://doi.org/10.3109/07420521003663801
  8. McClung CA. Circadian genes, rhythms and the biology of mood disorders. Pharmacol Ther 2007;114:222-232. https://doi.org/10.1016/j.pharmthera.2007.02.003
  9. Lowrey PL, Takahashi JS. Genetics of circadian rhythms in mammalian model organisms. Adv Genet 2011;74:175-230. https://doi.org/10.1016/B978-0-12-387690-4.00006-4
  10. Dunlap JC. Molecular bases for circadian clocks. Cell 1999;96:271-290. https://doi.org/10.1016/S0092-8674(00)80566-8
  11. Hu Y, Shmygelska A, Tran D, Eriksson N, Tung JY, Hinds DA. GWAS of 89,283 individuals identifies genetic variants associated with self-reporting of being a morning person. Nat Commun 2016;7:10448. https://doi.org/10.1038/ncomms10448
  12. Jones SE, Tyrrell J, Wood AR, Beaumont RN, Ruth KS, Tuke MA, et al. Genome-wide association analyses in 128,266 individuals identifies new morningness and sleep duration loci. PLoS Genet 2016;12:e1006125. https://doi.org/10.1371/journal.pgen.1006125
  13. Lane JM, Vlasac I, Anderson SG, Kyle SD, Dixon WG, Bechtold DA, et al. Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank. Nat Commun 2016;7:10889. https://doi.org/10.1038/ncomms10889
  14. Kalmbach DA, Schneider LD, Cheung J, Bertrand SJ, Kariharan T, Pack AI, et al. Genetic basis of chronotype in humans: insights from three landmark GWAS. Sleep 2017;40:zsw048.
  15. Jones SE, Lane JM, Wood AR, van Hees VT, Tyrrell J, Beaumont RN, et al. Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms. Nat Commun 2019;10:343. https://doi.org/10.1038/s41467-018-08259-7
  16. Park M, Kim SA, Yee J, Shin J, Lee KY, Joo EJ. Significant role of gene-gene interactions of clock genes in mood disorder. J Affect Disord 2019;257:510-517. https://doi.org/10.1016/j.jad.2019.06.056
  17. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81:559-575. https://doi.org/10.1086/519795
  18. Gui J, Moore JH, Williams SM, Andrews P, Hillege HL, van der Harst P, et al. A simple and computationally efficient approach to multifactor dimensionality reduction analysis of gene-gene interactions for quantitative traits. PLoS One 2013;8:e66545. https://doi.org/10.1371/journal.pone.0066545
  19. Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, et al. Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 2001;69:138-147. https://doi.org/10.1086/321276
  20. Katzenberg D, Young T, Finn L, Lin L, King DP, Takahashi JS, et al. A CLOCK polymorphism associated with human diurnal preference. Sleep 1998;21:569-576. https://doi.org/10.1093/sleep/21.6.569
  21. Robilliard DL, Archer SN, Arendt J, Lockley SW, Hack LM, English J, et al. The 3111 Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects. J Sleep Res 2002;11:305-312. https://doi.org/10.1046/j.1365-2869.2002.00320.x
  22. Adams CD, Jordahl KM, Copeland W, Mirick DK, Song X, Sather CL, et al. Nightshift work, chronotype, and genome-wide DNA methylation in blood. Epigenetics 2017;12:833-840. https://doi.org/10.1080/15592294.2017.1366407
  23. Pedrazzoli M, Louzada FM, Pereira DS, Benedito-Silva AA, Lopez AR, Martynhak BJ, et al. Clock polymorphisms and circadian rhythms phenotypes in a sample of the Brazilian population. Chronobiol Int 2007;24:1-8. https://doi.org/10.1080/07420520601139789
  24. 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:101-104. https://doi.org/10.1002/ajmg.b.30110
  25. Archer SN, Robilliard DL, Skene DJ, Smits M, Williams A, Arendt J, et al. A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep 2003;26:413-415. https://doi.org/10.1093/sleep/26.4.413
  26. Pereira DS, Tufik S, Louzada FM, Benedito-Silva AA, Lopez AR, Lemos NA, et al. Association of the length polymorphism in the human Per3 gene with the delayed sleep-phase syndrome: does latitude have an influence upon it? Sleep 2005;28:29-32.
  27. 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;14:293-297. https://doi.org/10.1111/j.1365-2869.2005.00471.x
  28. 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;51:1122-1125. https://doi.org/10.1007/s10038-006-0060-y
  29. Viola AU, Archer SN, Groeger JA, Skene DJ, Von Schantz M, Dijk DJ. Polymorphism in the clock gene PER3 predicts sleep structure and EEG power spectra. J Sleep Res 2006;15:53. https://doi.org/10.1111/j.1365-2869.2006.00540_24.x
  30. Satoh K, Mishima K, Inoue Y, Ebisawa T, Shimizu T. Two pedigrees of familial advanced sleep phase syndrome in Japan. Sleep 2003;26:416-417. https://doi.org/10.1093/sleep/26.4.416
  31. Emmanuel P, von Schantz M. Absence of morningness alleles in non-European populations. Chronobiol Int 2018;35:1758-1761. https://doi.org/10.1080/07420528.2018.1506928
  32. Lee HJ, Paik JW, Kang SG, Lim SW, Kim L. Allelic variants interaction of CLOCK gene and G-protein beta3 subunit gene with diurnal preference. Chronobiol Int 2007;24:589-597. https://doi.org/10.1080/07420520701534632
  33. Song HM, Cho CH, Lee HJ, Moon JH, Kang SG, Yoon HK, et al. Association of CLOCK, ARNTL, PER2, and GNB3 polymorphisms with diurnal preference in a Korean population. Chronobiol Int 2016;33:1455-1463. https://doi.org/10.1080/07420528.2016.1231199
  34. Pedrazzoli M, Secolin R, Esteves LO, Pereira DS, Koike Bdel V, Louzada FM, et al. Interactions of polymorphisms in different clock genes associated with circadian phenotypes in humans. Genet Mol Biol 2010;33:627-632. https://doi.org/10.1590/S1415-47572010005000092
  35. Liu AC, Tran HG, Zhang EE, Priest AA, Welsh DK, Kay SA. Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms. PLoS Genet 2008;4:e1000023. https://doi.org/10.1371/journal.pgen.1000023
  36. Cho H, Zhao X, Hatori M, Yu RT, Barish GD, Lam MT, et al. Regulation of circadian behaviour and metabolism by REV-ERBalpha and REV-ERB-beta. Nature 2012;485:123-127. https://doi.org/10.1038/nature11048
  37. Kang JI, Park CI, Namkoong K, Kim SJ. Associations between polymorphisms in the NR1D1 gene encoding for nuclear receptor REV-ERBalpha and circadian typologies. Chronobiol Int 2015;32:568-572. https://doi.org/10.3109/07420528.2015.1006327
  38. Jankowski KS, Dmitrzak-Weglarz M. ARNTL, CLOCK and PER3 polymorphisms: links with chronotype and affective dimensions. Chronobiol Int 2017;34:1105-1113. https://doi.org/10.1080/07420528.2017.1343341
  39. Barclay NL, Eley TC, Mill J, Wong CC, Zavos HM, Archer SN, et al. Sleep quality and diurnal preference in a sample of young adults: associations with 5HTTLPR, PER3, and CLOCK 3111. Am J Med Genet B Neuropsychiatr Genet 2011;156B:681-690.
  40. Osland TM, Bjorvatn BR, Steen VM, Pallesen S. Association study of a variable-number tandem repeat polymorphism in the clock gene PERIOD3 and chronotype in Norwegian university students. Chronobiol Int 2011;28:764-770. https://doi.org/10.3109/07420528.2011.607375
  41. Perea CS, Nino CL, Lopez-Leon S, Gutierrez R, Ojeda D, Arboleda H, et al. Study of a functional polymorphism in the PER3 gene and diurnal preference in a Colombian sample. Open Neurol J 2014;8:7-10. https://doi.org/10.2174/1874205X01408010007
  42. An H, Zhu Z, Zhou C, Geng P, Xu H, Wang H, et al. Chronotype and a PERIOD3 variable number tandem repeat polymorphism in Han Chinese pilots. Int J Clin Exp Med 2014;7:3770-3776.
  43. Hida A, Kitamura S, Kadotani H, Uchiyama M, Ebisawa T, Inoue Y, et al. Lack of association between PER3 variable number tandem repeat and circadian rhythm sleep-wake disorders. Hum Genome Var 2018;5:17. https://doi.org/10.1038/s41439-018-0017-7
  44. Chang AM, Buch AM, Bradstreet DS, Klements DJ, Duffy JF. Human diurnal preference and circadian rhythmicity are not associated with the CLOCK 3111C/T gene polymorphism. J Biol Rhythms 2011;26:276-279. https://doi.org/10.1177/0748730411402026
  45. Choub A, Mancuso M, Coppede F, LoGerfo A, Orsucci D, Petrozzi L, et al. Clock T3111C and Per2 C111G SNPs do not influence circadian rhythmicity in healthy Italian population. Neurol Sci 2011;32:89-93.
  46. 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. https://doi.org/10.1111/jsr.12144
  47. Lee HJ, Kim L, Kang SG, Yoon HK, Choi JE, Park YM, et al. PER2 variation is associated with diurnal preference in a Korean young population. Behav Genet 2011;41:273-277. https://doi.org/10.1007/s10519-010-9396-3
  48. Matsuo I, Iijima N, Takumi K, Higo S, Aikawa S, Anzai M, et al. Characterization of sevoflurane effects on Per2 expression using ex vivo bioluminescence imaging of the suprachiasmatic nucleus in transgenic rats. Neurosci Res 2016;107:30-37. https://doi.org/10.1016/j.neures.2015.11.010
  49. Chang AM, Duffy JF, Buxton OM, Lane JM, Aeschbach D, Anderson C, et al. Chronotype genetic variant in PER2 is associated with intrinsic Circadian period in humans. Sci Rep 2019;9:5350. https://doi.org/10.1038/s41598-019-41712-1
  50. Kunorozva L, Stephenson KJ, Rae DE, Roden LC. Chronotype and PERIOD3 variable number tandem repeat polymorphism in individual sports athletes. Chronobiol Int 2012;29:1004-1010. https://doi.org/10.3109/07420528.2012.719966
  51. Lazar AS, Slak A, Lo JC, Santhi N, von Schantz M, Archer SN, et al. Sleep, diurnal preference, health, and psychological well-being: a prospective single-allelic-variation study. Chronobiol Int 2012;29:131-146. https://doi.org/10.3109/07420528.2011.641193
  52. Silva A, Santos MJ, Koike BD, Moreira MS, Gitai DL, de Miranda Coelho JA, et al. Melatonin receptor 1B -1193T > C polymorphism is associated with diurnal preference and sleep habits. Sleep Med 2019;53:106-114. https://doi.org/10.1016/j.sleep.2018.09.023
  53. Johansson C, Willeit M, Aron L, Smedh C, Ekholm J, Paunio T, et al. Seasonal affective disorder and the G-protein beta-3-subunit C825T polymorphism. Biol Psychiatry 2004;55:317-319. https://doi.org/10.1016/S0006-3223(03)00640-1
  54. Bass J, Takahashi JS. Circadian integration of metabolism and energetics. Science 2010;330:1349-1354. https://doi.org/10.1126/science.1195027
  55. Feng D, Lazar MA. Clocks, metabolism, and the epigenome. Mol Cell 2012;47:158-167. https://doi.org/10.1016/j.molcel.2012.06.026
  56. Ioannidis JP, Thomas G, Daly MJ. Validating, augmenting and refining genome-wide association signals. Nat Rev Genet 2009;10:318-329. https://doi.org/10.1038/nrg2544