생물정신의학 (Korean Journal of Biological Psychiatry)

  • 제26권2호
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  • Pages.88-93
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  • 2019
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  • 1225-8709(pISSN)
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  • 2005-7571(eISSN)
대한생물정신의학회 (The Korean Society of Biological Psychiatry)
권호 표지

NR3C1 Polymorphisms for Genetic Susceptibility to Schizophrenia

  • Park, Joo Seok (Department of Psychiatry, Kyung Hee University Hospital) ;
  • Lee, Sang Min (Department of Psychiatry, Kyung Hee University Hospital) ;
  • Kim, Jong Woo (Department of Psychiatry, Kyung Hee University Hospital) ;
  • Kang, Won Sub (Department of Psychiatry, Kyung Hee University Hospital)
  • 투고 : 2019.09.16
  • 심사 : 2019.09.25
  • 발행 : 2019.10.31
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초록

Objectives Psychological stress has been known to increase the risk of schizophrenia. Because stress responses are mainly mediated by cortisol, the action of the glucocorticoid receptors (Nuclear Receptor Subfamily 3 Group C Member 1, NR3C1) is possibly related to the pathogenesis of schizophrenia. In this study, we investigated the associations between polymorphisms of NR3C1 and schizophrenia. Methods Four single nucleotide polymorphisms (SNPs) (rs17100236, rs2963155, rs9324924, and rs7701443) of NR3C1 were genotyped in 208 patients with schizophrenia and 339 healthy individuals. A chi-square test was performed to test differences in allele distributions among groups. A multiple logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), and multiple inheritance models to analyze the associations between schizophrenia and SNPs (the dominant, recessive and additive models). Results The minor allele frequencies of two SNPs were significantly higher in the schizophrenia group than in those of the control group (rs2963155 G > A : 0.25 vs. 0.18, p = 0.0066 ; rs7701443 A > G : 0.40 vs. 0.33, p = 0.012). The genotype frequencies of two SNPs were found to be significantly different between patients with schizophrenia and controls in the dominant model (rs2963155 : AG/GG vs. AA, OR = 1.66, 95% CI = 1.16-2.38, p = 0.0055, rs7701443 : AG/AA vs. GG, OR = 1.61, 95% CI = 1.11-2.34, p = 0.01) and the log-additive model (rs2963155 : AG vs. GG vs. AA, OR = 1.54, 95% CI = 1.13-2.10, p = 0.0067). Conclusions This study showed significant associations between NR3C1 polymorphisms and schizophrenia. It suggests that NR3C1 may play a role in the pathogenesis of schizophrenia.

키워드

참고문헌

  1. Corcoran C, Walker E, Huot R, Mittal V, Tessner K, Kestler L, et al. The stress cascade and schizophrenia: etiology and onset. Schizophr Bull 2003;29:671-692. https://doi.org/10.1093/oxfordjournals.schbul.a007038
  2. Norman RM, Malla AK. Stressful life events and schizophrenia. I: a review of the research. Br J Psychiatry 1993;162:161-166. https://doi.org/10.1192/bjp.162.2.161
  3. Myin-Germeys I, van Os J, Schwartz JE, Stone AA, Delespaul PA. Emotional reactivity to daily life stress in psychosis. Arch Gen Psychiatry 2001;58:1137-1144. https://doi.org/10.1001/archpsyc.58.12.1137
  4. Green MJ, Girshkin L, Teroganova N, Quide Y. Stress, schizophrenia and bipolar disorder. Curr Top Behav Neurosci 2014;18:217-235. https://doi.org/10.1007/7854_2014_290
  5. Cotter D, Pariante CM. Stress and the progression of the developmental hypothesis of schizophrenia. Br J Psychiatry 2002;181:363-365. https://doi.org/10.1192/bjp.181.5.363
  6. Mondelli V, Dazzan P, Hepgul N, Di Forti M, Aas M, D'Albenzio A, et al. Abnormal cortisol levels during the day and cortisol awakening response in first-episode psychosis: the role of stress and of antipsychotic treatment. Schizophr Res 2010;116:234-242. https://doi.org/10.1016/j.schres.2009.08.013
  7. Lammers CH, Garcia-Borreguero D, Schmider J, Gotthardt U, Dettling M, Holsboer F, et al. Combined dexamethasone/corticotropinreleasing hormone test in patients with schizophrenia and in normal controls: II. Biol Psychiatry 1995;38:803-807. https://doi.org/10.1016/0006-3223(95)00065-8
  8. Gallagher P, Watson S, Smith MS, Young AH, Ferrier IN. Plasma cortisol-dehydroepiandrosterone (DHEA) ratios in schizophrenia and bipolar disorder. Schizophr Res 2007;90:258-265. https://doi.org/10.1016/j.schres.2006.11.020
  9. Venkatasubramanian G, Chittiprol S, Neelakantachar N, Shetty T, Gangadhar BN. Effect of antipsychotic treatment on Insulin-like growth factor-1 and cortisol in schizophrenia: a longitudinal study. Schizophr Res 2010;119:131-137. https://doi.org/10.1016/j.schres.2010.01.033
  10. Garner B, Phassouliotis C, Phillips LJ, Markulev C, Butselaar F, Bendall S, et al. Cortisol and dehydroepiandrosterone-sulphate levels correlate with symptom severity in first-episode psychosis. J Psychiatr Res 2011;45:249-255. https://doi.org/10.1016/j.jpsychires.2010.06.008
  11. Webster MJ, Knable MB, O'Grady J, Orthmann J, Weickert CS. Regional specificity of brain glucocorticoid receptor mRNA alterations in subjects with schizophrenia and mood disorders. Mol Psychiatry 2002;7:985-994. https://doi.org/10.1038/sj.mp.4001139
  12. Sinclair D, Fullerton JM, Webster MJ, Shannon Weickert C. Glucocorticoid receptor 1B and 1C mRNA transcript alterations in schizophrenia and bipolar disorder, and their possible regulation by GR gene variants. PLoS One 2012;7:e31720. https://doi.org/10.1371/journal.pone.0031720
  13. Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol 2013;132:1033-1044. https://doi.org/10.1016/j.jaci.2013.09.007
  14. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med 2005;353:1711-1723. https://doi.org/10.1056/NEJMra050541
  15. Bray PJ, Cotton RG. Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms. Hum Mutat 2003;21:557-568. https://doi.org/10.1002/humu.10213
  16. Pimm J, McQuillin A, Thirumalai S, Lawrence J, Quested D, Bass N, et al. The Epsin 4 gene on chromosome 5q, which encodes the clathrin-associated protein enthoprotin, is involved in the genetic susceptibility to schizophrenia. Am J Hum Genet 2005;76:902-907. https://doi.org/10.1086/430095
  17. Petryshen TL, Middleton FA, Tahl AR, Rockwell GN, Purcell S, Aldinger KA, et al. Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia. Mol Psychiatry 2005;10:1074-1088. https://doi.org/10.1038/sj.mp.4001739
  18. Paunio T, Ekelund J, Varilo T, Parker A, Hovatta I, Turunen JA, et al. Genome-wide scan in a nationwide study sample of schizophrenia families in Finland reveals susceptibility loci on chromosomes 2q and 5q. Hum Mol Genet 2001;10:3037-3048. https://doi.org/10.1093/hmg/10.26.3037
  19. Sklar P, Pato MT, Kirby A, Petryshen TL, Medeiros H, Carvalho C, et al. Genome-wide scan in Portuguese Island families identifies 5q31-5q35 as a susceptibility locus for schizophrenia and psychosis. Mol Psychiatry 2004;9:213-218. https://doi.org/10.1038/sj.mp.4001418
  20. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, et al. The structure of haplotype blocks in the human genome. Science 2002;296:2225-2229. https://doi.org/10.1126/science.1069424
  21. Perroud N, Paoloni-Giacobino A, Prada P, Olie E, Salzmann A, Nicastro R, et al. Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma. Transl Psychiatry 2011;1:e59. https://doi.org/10.1038/tp.2011.60
  22. Klengel T, Pape J, Binder EB, Mehta D. The role of DNA methylation in stress-related psychiatric disorders. Neuropharmacology 2014;80:115-132. https://doi.org/10.1016/j.neuropharm.2014.01.013
  23. van Rossum EF, Binder EB, Majer M, Koper JW, Ising M, Modell S, et al. Polymorphisms of the glucocorticoid receptor gene and major depression. Biol Psychiatry 2006;59:681-688. https://doi.org/10.1016/j.biopsych.2006.02.007
  24. Galecka E, Szemraj J, Bienkiewicz M, Majsterek I, Przybylowska-Sygut K, Galecki P, et al. Single nucleotide polymorphisms of NR3C1 gene and recurrent depressive disorder in population of Poland. Mol Biol Rep 2013;40:1693-1699. https://doi.org/10.1007/s11033-012-2220-9
  25. Lahti J, Raikkonen K, Bruce S, Heinonen K, Pesonen AK, Rautanen A, et al. Glucocorticoid receptor gene haplotype predicts increased risk of hospital admission for depressive disorders in the Helsinki birth cohort study. J Psychiatr Res 2011;45:1160-1164. https://doi.org/10.1016/j.jpsychires.2011.03.008
  26. Szczepankiewicz A, Leszczynska-Rodziewicz A, Pawlak J, Rajewska-Rager A, Dmitrzak-Weglarz M, Wilkosc M, et al. Glucocorticoid receptor polymorphism is associated with major depression and predominance of depression in the course of bipolar disorder. J Affect Disord 2011;134:138-144. https://doi.org/10.1016/j.jad.2011.06.020
  27. Spijker AT, van Rossum EF, Hoencamp E, DeRijk RH, Haffmans J, Blom M, et al. Functional polymorphism of the glucocorticoid receptor gene associates with mania and hypomania in bipolar disorder. Bipolar Disord 2009;11:95-101. https://doi.org/10.1111/j.1399-5618.2008.00647.x
  28. Manenschijn L, van Rossum EF, Jetten AM, de Rooij SE, van Munster BC. Glucocorticoid receptor haplotype is associated with a decreased risk of delirium in the elderly. Am J Med Genet B Neuropsychiatr Genet 2011;156B:316-321.
  29. Desrivieres S, Lourdusamy A, Muller C, Ducci F, Wong CP, Kaakinen M, et al. Glucocorticoid receptor (NR3C1) gene polymorphisms and onset of alcohol abuse in adolescents. Addict Biol 2011;16:510-513. https://doi.org/10.1111/j.1369-1600.2010.00239.x
  30. Feng J, Zheng J, Bennett WP, Heston LL, Jones IR, Craddock N, et al. Five missense variants in the amino-terminal domain of the glucocorticoid receptor: no association with puerperal psychosis or schizophrenia. Am J Med Genet 2000;96:412-417. https://doi.org/10.1002/1096-8628(20000612)96:3<412::AID-AJMG33>3.0.CO;2-C
  31. Krupoves A, Mack D, Deslandres C, Seidman E, Amre DK. Variation in the glucocorticoid receptor gene (NR3C1) may be associated with corticosteroid dependency and resistance in children with Crohn's disease. Pharmacogenet Genomics 2011;21:454-460. https://doi.org/10.1097/FPC.0b013e3283476a01
  32. Yang G, Zou LP, He B, Ding YX, Wang J, Shi XY, et al. NR3C1 gene polymorphism for genetic susceptibility to infantile spasms in a Chinese population. Life Sci 2012;91:37-43. https://doi.org/10.1016/j.lfs.2012.06.010
  33. Yan YX, Dong J, Wu LJ, Shao S, Zhang J, Zhang L, et al. Associations between polymorphisms in the glucocorticoid-receptor gene and cardiovascular risk factors in a Chinese population. J Epidemiol 2013;23:389-395. https://doi.org/10.2188/jea.JE20130035
  34. Chen YF, Xu JH, Zou YF, Lian L, Wang F, Chen SY, et al. Association of glucocorticoid receptor gene polymorphisms with systemic lupus erythematosus in a Chinese population. Int J Rheum Dis 2017;20:2053-2061. https://doi.org/10.1111/1756-185X.13191
  35. Xue L, Li C, Wang Y, Sun W, Ma C, He Y, et al. Single nucleotide polymorphisms in non-coding region of the glucocorticoid receptor gene and prednisone response in childhood acute lymphoblastic leukemia. Leuk Lymphoma 2015;56:1704-1709. https://doi.org/10.3109/10428194.2014.951848
  36. Fang SY, Li CL, Liu XS, Chen F, Hua H. Correlation between polymorphisms of the NR3C1 gene and glucocorticoid effectiveness in patients with pemphigus vulgaris. Sci Rep 2017;7:11890. https://doi.org/10.1038/s41598-017-12255-0
  37. Mizoguchi K, Ishige A, Takeda S, Aburada M, Tabira T. Endogenous glucocorticoids are essential for maintaining prefrontal cortical cognitive function. J Neurosci 2004;24:5492-5499. https://doi.org/10.1523/JNEUROSCI.0086-04.2004
  38. Kumsta R, Entringer S, Koper JW, van Rossum EF, Hellhammer DH, Wust S. Working memory performance is associated with common glucocorticoid receptor gene polymorphisms. Neuropsychobiology 2010;61:49-56. https://doi.org/10.1159/000262180
  39. El-Hage W, Phillips ML, Radua J, Gohier B, Zelaya FO, Collier DA, et al. Genetic modulation of neural response during working memory in healthy individuals: interaction of glucocorticoid receptor and dopaminergic genes. Mol Psychiatry 2013;18:174-182. https://doi.org/10.1038/mp.2011.145
  40. Van Craenenbroeck K, De Bosscher K, Vanden Berghe W, Vanhoenacker P, Haegeman G. Role of glucocorticoids in dopamine-related neuropsychiatric disorders. Mol Cell Endocrinol 2005;245:10-22. https://doi.org/10.1016/j.mce.2005.10.007