Sleep Medicine and Psychophysiology (수면정신생리)

KOREAN ACADEMY OF SLEEP MEDICINE (대한수면의학회)
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Association of the RORA Gene Polymorphism and Seasonal Variations in Mood and Behavior

RORA 유전자 다형성과 기분 및 행동의 계절성 변동의 연관성

  • Kim, Hae-In (Department of Psychiatry, Korea University College of Medicine) ;
  • So, Soo-Jung (Department of Psychiatry, Korea University College of Medicine) ;
  • Yang, Hee Jung (Department of Psychiatry, Korea University College of Medicine) ;
  • Song, Hyun Mi (Department of Psychiatry, Korea University College of Medicine) ;
  • Moon, Joung Ho (Department of Psychiatry, Korea University College of Medicine) ;
  • Yoon, Ho-Kyoung (Department of Psychiatry, Korea University College of Medicine) ;
  • Kang, Seung-Gul (Department of Psychiatry, Gil Medical Center, Gachon Medical School) ;
  • Park, Young-Min (Department of Psychiatry, Inje University College of Medicine, Ilsan Paik Hospital) ;
  • Lee, Seung-Hwan (Department of Psychiatry, Inje University College of Medicine, Ilsan Paik Hospital) ;
  • Kim, Leen (Department of Psychiatry, Korea University College of Medicine) ;
  • Lee, Heon-Jeong (Department of Psychiatry, Korea University College of Medicine)
  • 김해인 (고려대학교 의과대학 정신건강의학교실) ;
  • 소수정 (고려대학교 의과대학 정신건강의학교실) ;
  • 양희정 (고려대학교 의과대학 정신건강의학교실) ;
  • 송현미 (고려대학교 의과대학 정신건강의학교실) ;
  • 문정호 (고려대학교 의과대학 정신건강의학교실) ;
  • 윤호경 (고려대학교 의과대학 정신건강의학교실) ;
  • 강승걸 (가천대학교 의과대학 정신건강의학교실) ;
  • 박영민 (인제대학교 의과대학 정신건강의학교실) ;
  • 이승환 (인제대학교 의과대학 정신건강의학교실) ;
  • 김린 (고려대학교 의과대학 정신건강의학교실) ;
  • 이헌정 (고려대학교 의과대학 정신건강의학교실)
  • Received : 2013.10.29
  • Accepted : 2013.11.27
  • Published : 2013.12.31
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Abstract

Objectives: Several evidence has been suggested that the circadian gene variants contribute to the pathogenesis of seasonal affective disorder. In this study, we aimed to investigate the polymorphism in RORA (Retinoid-related orphan receptor A) gene in relation to seasonal variations among healthy young adults in Seoul, Korea. Methods: A total of 507 young healthy adult subjects were recruited by advertisement. Seasonal variations were assessed by the Seasonality Pattern Assessment Questionnaire (SPAQ). Single-nucleotide polymorphism in the RORA rs11071547 gene was genotyped by PCR in 507 individuals. Considering summer type as confounding factor, we conducted analysis 478 subjects except 29 subjects of summer type. The Chi-square test was conducted to compare differences between groups of seasonals and non-seasonals. Association between genotypes and Global Seasonality Score (GSS) were tested using ANCOVA (Analysis of covariance). Results: In this sample, the prevalence of SAD was 12.1% (winter type 9.3%, summer type 2.8%). There is no significant difference in genotyping distribution of RORA rs11071547 between groups of seasonals and non-seasonals. Global seasonality score (GSS) and scores of all subscales except body weight and appetite were not significantly different between the group with C allele homozygote and the group with T allele homozygote and heterozygote (p-value 0.138). Scores of body weight and appetite were significantly higher in group with C allele homozygotes. Conclusion: These results suggest that RORA gene polymorphism play a role in seasonal variations in appetite and body weight and is associated with susceptibility to seasonal affective disorder in some degree in the population studied.

목 적 : 일주기 유전자 다형성이 계절성 기분 장애의 발병 기전과 연관이 있다는 여러 연구 결과들이 보고되었다. 본 연구에서는 한국에 거주하는 건강한 성인을 대상으로 RORA (Retinoid-related orphan receptor A)유전자의 다형성과 계절성 변동의 관계를 살펴보고자 하였다. 방 법 : 신문 광고를 통해 모집한 507명의 지역사회 인구를 대상으로 하였다. 기분과 행동의 계절적 변동은 Seasonality Pattern Assessment Questionnaire(SPAQ)를 이용하여 평가하였다. RORA rs11071547 SNP는 PCR을 이용하여 유전자형 분석을 하였다. 여름형은 교란 요소로 작용할 것으로 판단되어, 29명의 여름형은 제외한 총 478명의 대상자를 분석하였다. 계절성군과 비계절성군의 유전자형 분포의 비교는 Chi-square test를 이용하였고, 전반적 계절성 점수(Global seasonality score, GSS)와 RORA rs11071547의 연관성은 ANCOVA로 분석하였다. 결 과 : 연구 참여자 507명 중 12.1%(겨울형 9.3%, 여름형 2.8%)가 SAD에 해당하였다. 계절성군과 비계절성군간의 RORA rs11071547의 유전자형 분포는 통계적으로 유의한 차이는 없었다. 전반적 계절성 점수(GSS)와 세부 항목인 수면시간, 사회활동, 기분, 에너지 수준에서 유의한 차이는 관찰되지 않았다. 그러나 세부 항목 중 체중과 식욕에서는 C 대립유전자 동형접함체군에서 유의하게 점수가 높은 양상을 관찰할 수 있었다(p=0.026, p=0.034). 결 론 : 본 연구에 참여한 대상자들에서 RORA 유전자 다형성이 체중과 식욕의 계절성 변화에 주요한 역할을 하며, 계절성 기분 장애의 감수성과도 어느 정도 연관이 있을 것으로 생각된다.

Keywords

References

  1. Akashi M, Takumi T. The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1. Nat Struct Mol Biol 2005;12:441-448. https://doi.org/10.1038/nsmb925
  2. Benedetti F, Dallaspezia S, Colombo C, Pirovano A, Marino E, Smeraldi E. A length polymorphism in the circadian clock gene Per3 influences age at onset of bipolar disorder. Neurosci Lett 2008; 445:184-187. https://doi.org/10.1016/j.neulet.2008.09.002
  3. Benedetti F, Serretti A, Colombo C, Barbini B, Lorenzi C, Campori E, et al. Influence of CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence in bipolar depression. Am J Med Genet B Neuropsychiatr Genet 2003;123B:23-26. https://doi.org/10.1002/ajmg.b.20038
  4. Boukhtouche F, Vodjdani G, Jarvis CI, Bakouche J, Staels B, Mallet J, et al. Human retinoic acid receptor-related orphan receptor alpha1 overexpression protects neurones against oxidative stress-induced apoptosis. J Neurochem 2006;96:1778-1789. https://doi.org/10.1111/j.1471-4159.2006.03708.x
  5. Boyce P, Parker G. Seasonal affective disorder in the southern hemisphere. Am J Psychiatry 1988;145:96-99. https://doi.org/10.1176/ajp.145.1.96
  6. Dzhagalov I, Giguere V, He YW. Lymphocyte development and function in the absence of retinoic acid-related orphan receptor alpha. J Immunol 2004;173:2952-2959. https://doi.org/10.4049/jimmunol.173.5.2952
  7. Frederic F, Chianale C, Oliver C, Mariani J. Enhanced endocrine response to novel environment stress and lack of corticosterone circadian rhythm in staggerer (Rora sg/sg) mutant mice. J Neurosci Res 2006;83:1525-1532. https://doi.org/10.1002/jnr.20843
  8. Giguere V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G. Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev 1994;8:538-553. https://doi.org/10.1101/gad.8.5.538
  9. Ino H. Immunohistochemical characterization of the orphan nuclear receptor ROR alpha in the mouse nervous system. J Histochem Cytochem 2004;52:311-323. https://doi.org/10.1177/002215540405200302
  10. Jarvis CI, Staels B, Brugg B, Lemaigre-Dubreuil Y, Tedgui A, Mariani J. Age-related phenotypes in the staggerer mouse expand the RORalpha nuclear receptor's role beyond the cerebellum. Mol Cell Endocrinol 2002;186:1-5. https://doi.org/10.1016/S0303-7207(01)00668-2
  11. 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
  12. Johansson C, Willeit M, Smedh C, Ekholm J, Paunio T, Kieseppa T, et al. Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference. Neuropsychopharmacology 2003;28:734-739. https://doi.org/10.1038/sj.npp.1300121
  13. Kamphuis W, Cailotto C, Dijk F, Bergen A, Buijs RM. Circadian expression of clock genes and clock-controlled genes in the rat retina. Biochem Biophys Res Commun 2005;330:18-26. https://doi.org/10.1016/j.bbrc.2005.02.118
  14. Kasper S, Wehr TA, Bartko JJ, Gaist PA, Rosenthal NE. Epidemiological findings of seasonal changes in mood and behavior. A telephone survey of Montgomery County, Maryland. Arch Gen Psychiatry 1989;46:823-833. https://doi.org/10.1001/archpsyc.1989.01810090065010
  15. Kishi T, Kitajima T, Ikeda M, Yamanouchi Y, Kinoshita Y, Kawashima K, et al. Association study of clock gene (CLOCK) and schizophrenia and mood disorders in the Japanese population. Eur Arch Psychiatry Clin Neurosci 2009;259:293-297. https://doi.org/10.1007/s00406-009-0869-4
  16. Kishi T, Kitajima T, Ikeda M, Yamanouchi Y, Kinoshita Y, Kawashima K, et al. Association analysis of nuclear receptor Rev-erb alpha gene (NR1D1) with mood disorders in the Japanese population. Neurosci Res 2008;62:211-215. https://doi.org/10.1016/j.neures.2008.08.008
  17. Kopmels B, Mariani J, Delhaye-Bouchaud N, Audibert F, Fradelizi D, Wollman EE. Evidence for a hyperexcitability state of staggerer mutant mice macrophages. J Neurochem 1992;58:192-199. https://doi.org/10.1111/j.1471-4159.1992.tb09295.x
  18. Kripke DF, Nievergelt CM, Joo E, Shekhtman T, Kelsoe JR. Circadian polymorphisms associated with affective disorders. J Circadian Rhythms 2009;7:2. https://doi.org/10.1186/1740-3391-7-2
  19. Lavebratt C, Sjoholm LK, Partonen T, Schalling M, Forsell Y. PER2 variantion is associated with depression vulnerability. Am J Med Genet B Neuropsychiatr Genet 2010a;153B:570-581. https://doi.org/10.1002/ajmg.b.31021
  20. Lavebratt C, Sjoholm LK, Soronen P, Paunio T, Vawter MP, Bunney WE, et al. CRY2 is associated with depression. PLoS One 2010b; 5:e9407. https://doi.org/10.1371/journal.pone.0009407
  21. Lee HJ, Sung SM, Han CS, Kim YK, Kim SH, Lee MS, et al. G-protein beta3 subunit C825T polymorphism tends to be associated with seasonal variation in young male college students. Neuropsychobiology 2005;52:135-139. https://doi.org/10.1159/000087559
  22. Lee HJ, Sung SM, Lim SW, Paik JW, Leen K. Seasonality associated with the serotonin 2A receptor -1438 A/G polymorphism. J Affect Disord 2006;95:145-148. https://doi.org/10.1016/j.jad.2006.05.001
  23. Lee KY, Song JY, Kim SH, Kim SC, Joo EJ, Ahn YM, et al. Association between CLOCK 3111T/C and preferred circadian phase in Korean patients with bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:1196-1201. https://doi.org/10.1016/j.pnpbp.2010.06.010
  24. Lewy AJ, Sack RL, Singer CM, White DM, Hoban TM. Winter depression and the phase-shift hypothesis for bright light's therapeutic effects: history, theory, and experimental evidence. J Biol Rhythms 1988;3:121-134. https://doi.org/10.1177/074873048800300203
  25. Logue MW, Baldwin C, Guffanti G, Melista E, Wolf EJ, Reardon AF, et al. A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus. Mol Psychiatry 2013;18:937-942 https://doi.org/10.1038/mp.2012.113
  26. Magnusson A. An overview of epidemiological studies on seasonal affective disorder. Acta Psychiatr Scand 2000;101:176-184. https://doi.org/10.1034/j.1600-0447.2000.101003176.x
  27. Mansour HA, Talkowski ME, Wood J, Chowdari KV, McClain L, Prasad K, et al. Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia. Bipolar Disord 2009;11:701-710. https://doi.org/10.1111/j.1399-5618.2009.00756.x
  28. Mansour HA, Wood J, Logue T, Chowdari KV, Dayal M, Kupfer DJ, et al. Association study of eight circadian genes with bipolar I disorder, schizoaffective disorder and schizophrenia. Genes Brain Behav 2006;5:150-157. https://doi.org/10.1111/j.1601-183X.2005.00147.x
  29. McGrath CL, Glatt SJ, Sklar P, Le-Niculescu H, Kuczenski R, Doyle AE, et al. Evidence for genetic association of RORB with bipolar disorder. BMC Psychiatry 2009;9:70. https://doi.org/10.1186/1471-244X-9-70
  30. Paik JW, Lee HJ, Kang SG, Lim SW, Lee MS, Kim L. CLOCK gene 3111C/T polymorphism is not associated with seasonal variations in mood and behavior in Korean college students. Psychiatry Clin Neurosci 2007;61:124-126. https://doi.org/10.1111/j.1440-1819.2007.01621.x
  31. Partonen T, Treutlein J, Alpman A, Frank J, Johansson C, Depner M, et al. Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression. Ann Med 2007;39:229-238. https://doi.org/10.1080/07853890701278795
  32. Rosenthal N, Genhart M, Sack D, Skwerer R, Wehr T. Seasonal affective disorder and its relevance for the understanding and treatment of bulimia. The Psychobiology of Bulimia 1987;205-228.
  33. Rosenthal NE, Sack DA, Gillin JC, Lewy AJ, Goodwin FK, Davenport Y, et al. Seasonal affective disorder. A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 1984;41:72-80. https://doi.org/10.1001/archpsyc.1984.01790120076010
  34. Shi J, Wittke-Thompson JK, Badner JA, Hattori E, Potash JB, Willour VL, et al. Clock genes may influence bipolar disorder susceptibility and dysfunctional circadian rhythm. Am J Med Genet B Neuropsychiatr Genet 2008;147B:1047-1055. https://doi.org/10.1002/ajmg.b.30714
  35. Sjoholm LK, Backlund L, Cheteh EH, Ek IR, Frisen L, Schalling M, et al. CRY2 is associated with rapid cycling in bipolar disorder patients. PLoS One 2010;5:e12632. https://doi.org/10.1371/journal.pone.0012632
  36. Soria V, Martinez-Amoros E, Escaramis G, Valero J, Perez-Egea R, Garcia C, et al. 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;35:1279-1289. https://doi.org/10.1038/npp.2009.230
  37. Takahashi JS, Hong HK, Ko CH, McDearmon EL. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet 2008;9:764-775. https://doi.org/10.1038/nrg2430
  38. Tosini G, Davidson AJ, Fukuhara C, Kasamatsu M, Castanon-Cervantes O. Localization of a circadian clock in mammalian photoreceptors. FASEB J 2007;21:3866-3871. https://doi.org/10.1096/fj.07-8371com
  39. Ueda HR, Chen W, Adachi A, Wakamatsu H, Hayashi S, Takasugi T, et al. A transcription factor response element for gene expression during circadian night. Nature 2002;418:534-539. https://doi.org/10.1038/nature00906
  40. Utge SJ, Soronen P, Loukola A, Kronholm E, Ollila HM, Pirkola S, et al. Systematic analysis of circadian genes in a population-based sample reveals association of TIMELESS with depression and sleep disturbance. PloS One 2010;5:e9259. https://doi.org/10.1371/journal.pone.0009259
  41. Wehr TA, Sack DA, Rosenthal NE. Seasonal affective disorder with summer depression and winter hypomania. Am J Psychiatry 1987;144:1602-1603. https://doi.org/10.1176/ajp.144.12.1602
  42. Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M, et al. Nuclear receptor expression links the circadian clock to metabolism. Cell 2006;126:801-810. https://doi.org/10.1016/j.cell.2006.06.050

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