Korean Journal of Biological Psychiatry (생물정신의학)

The Korean Society of Biological Psychiatry (대한생물정신의학회)
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No Association between (AAT)n Repeat Polymorphisms in the Cannabinoid Receptor 1 Gene and Smooth Pursuit Eye Movement Abnormality in Korean Patients with Schizophrenia

한국인 조현병 환자에서CNR1 유전자의 (AAT)n 삼핵산 반복 다형성과 안구추적운동 이상에 대한 연합 연구

  • Kim, Min Jae (Department of Psychiatry, Soonchunhyang University Seoul Hospital, College of Medicine, Soonchunhyang University) ;
  • Kim, Chae-Ri (Department of Psychiatry, Soonchunhyang University Seoul Hospital, College of Medicine, Soonchunhyang University) ;
  • Park, Jin Wan (Department of Psychiatry, Soonchunhyang University Seoul Hospital, College of Medicine, Soonchunhyang University) ;
  • Pak, Doo Hyun (Department of Psychiatry, Soonchunhyang University Seoul Hospital, College of Medicine, Soonchunhyang University) ;
  • Shin, Hyoung Doo (Department of Life Science, Sogang University) ;
  • Choi, Ihn-Geun (Department of Neuropsychiatry, Kangnam Sacred Heart Hospital, Hallym University College of Medicine) ;
  • Hahn, Sang Woo (Department of Psychiatry, Soonchunhyang University Seoul Hospital, College of Medicine, Soonchunhyang University) ;
  • Hwang, Jaeuk (Department of Psychiatry, Soonchunhyang University Seoul Hospital, College of Medicine, Soonchunhyang University) ;
  • Lee, Yeon Jung (Department of Psychiatry, Soonchunhyang University Seoul Hospital, College of Medicine, Soonchunhyang University) ;
  • Woo, Sung-Il (Department of Psychiatry, Soonchunhyang University Seoul Hospital, College of Medicine, Soonchunhyang University)
  • 김민재 (순천향대학교 의과대학 순천향대학교병원 정신건강의학교실,) ;
  • 김채리 (순천향대학교 의과대학 순천향대학교병원 정신건강의학교실,) ;
  • 박진완 (순천향대학교 의과대학 순천향대학교병원 정신건강의학교실,) ;
  • 백두현 (순천향대학교 의과대학 순천향대학교병원 정신건강의학교실,) ;
  • 신형두 (서강대학교 생명공학과) ;
  • 최인근 (한림대학교 의과대학 강남성심병원 정신건강의학교실) ;
  • 한상우 (순천향대학교 의과대학 순천향대학교병원 정신건강의학교실,) ;
  • 황재욱 (순천향대학교 의과대학 순천향대학교병원 정신건강의학교실,) ;
  • 이연정 (순천향대학교 의과대학 순천향대학교병원 정신건강의학교실,) ;
  • 우성일 (순천향대학교 의과대학 순천향대학교병원 정신건강의학교실,)
  • Received : 2016.07.05
  • Accepted : 2016.08.04
  • Published : 2016.11.30
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Abstract

Objectives According to previous studies, the cannabinoid receptor 1 (CNR1) gene could be an important candidate gene for schizophrenia. Some studies have linked the (AAT)n trinucleotide repeat polymorphism in CNR1 gene with the risk of schizophrenia. Meanwhile, smooth pursuit eye movement (SPEM) has been regarded as one of the most consistent endophenotypes of schizophrenia. In this study, we investigated the association between the (AAT)n trinucleotide repeats in CNR1 gene and SPEM abnormality in Korean patients with schizophrenia. Methods We measured SPEM function in 167 Korean patients with schizophrenia (84 male, 83 female) and they were divided according to SPEM function into two groups, good and poor SPEM function groups. We also investigated allele frequencies of (AAT)n repeat polymorphisms on CNR1 gene in each group. A logistic regression analysis was performed to find the association between SPEM abnormality and the number of (AAT)n trinucleotide repeats. Results The natural logarithm value of signal/noise ratio (Ln S/N ratio) of the good SPEM function group was $4.34{\pm}0.29$ and that of the poor SPEM function group was $3.21{\pm}0.70$. In total, 7 types of trinucleotide repeats were identified, each containing 7, 10, 11, 12, 13, 14, and 15 repeats, respectively. In the patients with $(AAT)7$ allele, the distributions of the good and poor SPEM function groups were 18 (11.1%) and 19 (11.0%) respectively. In the patients with $(AAT)_{10}$ allele, $(AAT)_{11}$ allele, $(AAT)_{12}$ allele, $(AAT)_{13}$ allele, $(AAT)_{14}$ allele and $(AAT)_{15}$ allele, the distributions of good and poor SPEM function groups were 13 (8.0%) and 12 (7.0%), 4 (2.5%) and 6 (3.5%), 31 (19.8%) and 35 (20.3%), 51 (31.5%) and 51 (29.7%), 36 (22.2%) and 45 (26.2%), 9 (5.6%) and 4 (2.3%) respectively. As the number of (AAT) n repeat increased, there was no aggravation of abnormality of SPEM function. Conclusions There was no significant aggravation of SPEM abnormality along with the increase of number of (AAT)n trinucleotide repeats in the CNR1 gene in Korean patients with schizophrenia.

Keywords

References

  1. Karayiorgou M, Gogos JA. A turning point in schizophrenia genetics. Neuron 1997;19:967-979. https://doi.org/10.1016/S0896-6273(00)80390-6
  2. Doherty JL, O'Donovan MC, Owen MJ. Recent genomic advances in schizophrenia. Clin Genet 2012;81:103-109. https://doi.org/10.1111/j.1399-0004.2011.01773.x
  3. Halikas JA, Goodwin DW, Guze SB. Marihuana use and psychiatric illness. Arch Gen Psychiatry 1972;27:162-165. https://doi.org/10.1001/archpsyc.1972.01750260016003
  4. Johns A. Psychiatric effects of cannabis. Br J Psychiatry 2001;178:116-122. https://doi.org/10.1192/bjp.178.2.116
  5. Spencer DJ. Cannabis-induced psychosis. Int J Addict 1971;6:323-326. https://doi.org/10.3109/10826087109057790
  6. Andreasson S, Allebeck P, Engstrom A, Rydberg U. Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet 1987;2:1483-1486.
  7. van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol 2002;156:319-327. https://doi.org/10.1093/aje/kwf043
  8. Potvin S, Joyal CC, Pelletier J, Stip E. Contradictory cognitive capacities among substance-abusing patients with schizophrenia: a meta-analysis. Schizophr Res 2008;100:242-251. https://doi.org/10.1016/j.schres.2007.04.022
  9. Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ 2002;325:1212-1213. https://doi.org/10.1136/bmj.325.7374.1212
  10. Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ 2005;330:11. https://doi.org/10.1136/bmj.38267.664086.63
  11. Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ 2002;325:1199. https://doi.org/10.1136/bmj.325.7374.1199
  12. D'Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu YT, et al. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 2004;29:1558-1572. https://doi.org/10.1038/sj.npp.1300496
  13. Rais M, Cahn W, Van Haren N, Schnack H, Caspers E, Hulshoff Pol H, et al. Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients. Am J Psychiatry 2008;165:490-496. https://doi.org/10.1176/appi.ajp.2007.07071110
  14. Wong DF, Kuwabara H, Horti AG, Raymont V, Brasic J, Guevara M, et al. Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR. Neuroimage 2010;52:1505-1513. https://doi.org/10.1016/j.neuroimage.2010.04.034
  15. Koethe D, Giuffrida A, Schreiber D, Hellmich M, Schultze-Lutter F, Ruhrmann S, et al. Anandamide elevation in cerebrospinal fluid in initial prodromal states of psychosis. Br J Psychiatry 2009;194:371-372. https://doi.org/10.1192/bjp.bp.108.053843
  16. Leweke FM, Giuffrida A, Koethe D, Schreiber D, Nolden BM, Kranaster L, et al. Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: impact of cannabis use. Schizophr Res 2007;94:29-36. https://doi.org/10.1016/j.schres.2007.04.025
  17. Fakhoury M. Role of the Endocannabinoid System in the Pathophysiology of Schizophrenia. Mol Neurobiol 2016 Jan 15 [Epub ahead of print]. http://dx.doi.org/10.110.1007/s12035-016-9697-5.
  18. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992;258:1946-1949. https://doi.org/10.1126/science.1470919
  19. Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 1995;215:89-97. https://doi.org/10.1006/bbrc.1995.2437
  20. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561-564. https://doi.org/10.1038/346561a0
  21. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61-65. https://doi.org/10.1038/365061a0
  22. Pazos MR, Nunez E, Benito C, Tolon RM, Romero J. Functional neuroanatomy of the endocannabinoid system. Pharmacol Biochem Behav 2005;81:239-247. https://doi.org/10.1016/j.pbb.2005.01.030
  23. Roche M, Finn DP. Brain CB2 Receptors: Implications for Neuropsychiatric Disorders. Pharmaceuticals (Basel) 2010;3:2517-2553. https://doi.org/10.3390/ph3082517
  24. Chavarria-Siles I, Contreras-Rojas J, Hare E, Walss-Bass C, Quezada P, Dassori A, et al. Cannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2008;147:279-284.
  25. Ujike H, Takaki M, Nakata K, Tanaka Y, Takeda T, Kodama M, et al. CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Mol Psychiatry 2002;7:515-518. https://doi.org/10.1038/sj.mp.4001029
  26. Bae JS, Kim JY, Park BL, Kim JH, Kim B, Park CS, et al. Genetic association analysis of CNR1 and CNR2 polymorphisms with schizophrenia in a Korean population. Psychiatr Genet 2014;24:225-229.
  27. Kim JW, Roh YH, Kim MJ, Kim CR, Park BL, Bae JS, et al. Association Analysis between (AAT)n repeats in the cannabinoid receptor 1 gene and schizophrenia in a Korean population. Korean J Biol Psychiatry 2014;21:99-106.
  28. Krauzlis RJ. The control of voluntary eye movements: new perspectives. Neuroscientist 2005;11:124-137. https://doi.org/10.1177/1073858404271196
  29. Lencer R, Trillenberg P. Neurophysiology and neuroanatomy of smooth pursuit in humans. Brain Cogn 2008;68:219-228. https://doi.org/10.1016/j.bandc.2008.08.013
  30. Van Essen DC, Gallant JL. Neural mechanisms of form and motion processing in the primate visual system. Neuron 1994;13:1-10. https://doi.org/10.1016/0896-6273(94)90455-3
  31. Annese J, Gazzaniga MS, Toga AW. Localization of the human cortical visual area MT based on computer aided histological analysis. Cereb Cortex 2005;15:1044-1053. https://doi.org/10.1093/cercor/bhh205
  32. Braun DI, Boman DK, Hotson JR. Anticipatory smooth eye movements and predictive pursuit after unilateral lesions in human brain. Exp Brain Res 1996;110:111-116.
  33. Gagnon D, Paus T, Grosbras MH, Pike GB, O'Driscoll GA. Transcranial magnetic stimulation of frontal oculomotor regions during smooth pursuit. J Neurosci 2006;26:458-466. https://doi.org/10.1523/JNEUROSCI.2789-05.2006
  34. Lencer R, Nagel M, Sprenger A, Zapf S, Erdmann C, Heide W, et al. Cortical mechanisms of smooth pursuit eye movements with target blanking. An fMRI study. Eur J Neurosci 2004;19:1430-1436. https://doi.org/10.1111/j.1460-9568.2004.03229.x
  35. Nagel M, Sprenger A, Zapf S, Erdmann C, Kompf D, Heide W, et al. Parametric modulation of cortical activation during smooth pursuit with and without target blanking. an fMRI study. Neuroimage 2006;29:1319-1325. https://doi.org/10.1016/j.neuroimage.2005.08.050
  36. Ono S Das VE, Economides JR, Mustari MJ. Modeling of smooth pursuit-related neuronal responses in the DLPN and NRTP of the rhesus macaque. J Neurophysiol 2005;93:108-116. https://doi.org/10.1152/jn.00588.2004
  37. Cuthbert BN. The RDoC framework: facilitating transition from ICD/DSM to dimensional approaches that integrate neuroscience and psychopathology. World Psychiatry 2014;13:28-35. https://doi.org/10.1002/wps.20087
  38. Jang HJ, Moon HI, Lee YJ, Kim IY, Lee IS, Seo HG, et al. No Association between Val108/158Met Polymorphism on Catechol-O-Methyl Transferase (COMT) Gene and Smooth Pursuit Eye Movement (SPEM) Abnormality in Korean Schizophrenia Patients. Korean J Biol Psychiatry 2008;15:288-296.
  39. Lee CH, Park BL, Kim LH, Kim DH, Cho SH, Park JS, et al. Relationship between SNP A and P1763 polymorphisms on dystrobrevin binding protein 1 (DTNBP1) gene and smooth pursuit eye movement (SPEM) abnormality in Korean schizophrenic patients. Korean J Biol Psychiatry 2006;13:279-288.
  40. Lee YJ, Lee MK, Kim YJ, Han SW, Hwang J, Kim KH, et al. Association analysis between the G72/G30 single nucleotide polymorphisms (rs947267 and rs77829) and smooth pursuit eye movement (SPEM) abnormality of patients with schizophrenia in Korean population. Korean J Schzophr Res 2010;13:42-49.
  41. Kim JH, Park BL, Pasaje CF, Bae JS, Park CS, Cha B, et al. Lack of associations of neuregulin 1 variations with schizophrenia and smooth pursuit eye movement abnormality in a Korean population. J Mol Neurosci 2012;46:476-482. https://doi.org/10.1007/s12031-011-9619-y
  42. Pasaje CF, Bae JS, Park BL, Cheong HS, Kim JH, Park TJ, et al. Neuregulin 3 does not confer risk for schizophrenia and smooth pursuit eye movement abnormality in a Korean population. Genes Brain Behav 2011;10:828-833. https://doi.org/10.1111/j.1601-183X.2011.00722.x
  43. Shin HD, Park BL, Bae JS, Park TJ, Chun JY, Park CS, et al. Association of ZDHHC8 polymorphisms with smooth pursuit eye movement abnormality. Am J Med Genet B Neuropsychiatr Genet 2010;153B:1167-1172.
  44. Cheong HS, Park BL, Kim EM, Park CS, Sohn JW, Kim BJ, et al. Association of RANBP1 haplotype with smooth pursuit eye movement abnormality. Am J Med Genet B Neuropsychiatr Genet 2011;156B:67-71.
  45. Woo SI, Lee IS, Ha HB, Jung CY, Lee HC, Yum MK. Eye tracking abnormality in schizophrenic inpatients. Seoul J Psychiatry 1993;18:100-108.
  46. Jung CY, Woo SI, Park CS. Eye tracking abnormality in schizophrenia: follow up study after 4 months. J Korean Neuropsychiatr Assoc 1995;34:369-377.
  47. Vigano D, Guidali C, Petrosino S, Realini N, Rubino T, Di Marzo V, et al. Involvement of the endocannabinoid system in phencyclidineinduced cognitive deficits modelling schizophrenia. Int J Neuropsychopharmacol 2009;12:599-614. https://doi.org/10.1017/S1461145708009371
  48. Singer W. Neuronal synchrony: a versatile code for the definition of relations? Neuron 1999;24:49-65, 111-125. https://doi.org/10.1016/S0896-6273(00)80821-1
  49. Edwards CR, Skosnik PD, Steinmetz AB, O'Donnell BF, Hetrick WP. Sensory gating impairments in heavy cannabis users are associated with altered neural oscillations. Behav Neurosci 2009;123:894-904. https://doi.org/10.1037/a0016328
  50. Brookes MJ, Wood JR, Stevenson CM, Zumer JM, White TP, Liddle PF, et al. Changes in brain network activity during working memory tasks: a magnetoencephalography study. Neuroimage 2011;55:1804-1815. https://doi.org/10.1016/j.neuroimage.2010.10.074
  51. Skosnik PD, Cortes-Briones JA, Hajos M. It's All in the Rhythm: The role of cannabinoids in neural oscillations and psychosis. Biol Psychiatry 2016;79:568-577. https://doi.org/10.1016/j.biopsych.2015.12.011
  52. Skosnik PD, D'Souza DC, Steinmetz AB, Edwards CR, Vollmer JM, Hetrick WP, et al. The effect of chronic cannabinoids on broadband EEG neural oscillations in humans. Neuropsychopharmacology 2012;37:2184-2193. https://doi.org/10.1038/npp.2012.65
  53. Morrison PD, Nottage J, Stone JM, Bhattacharyya S, Tunstall N, Brenneisen R, ET al. Disruption of frontal $\Theta$ coherence by ${\Delta}9$-tetrahydrocannabinol is associated with positive psychotic symptoms. Neuropsychopharmacology 2011;36:827-836. https://doi.org/10.1038/npp.2010.222
  54. Dawson E, Gill M, Curtis D, Castle D, Hunt N, Murray R, et al. Genetic association between alleles of pancreatic phospholipase A2 gene and bipolar affective disorder. Psychiatr Genet 1995;5:177-180. https://doi.org/10.1097/00041444-199524000-00005
  55. Tsai SJ, Wang YC, Hong CJ. Association study of a cannabinoid receptor gene (CNR1) polymorphism and schizophrenia. Psychiatr Genet 2000;10:149-151. https://doi.org/10.1097/00041444-200010030-00008
  56. Martinez-Gras I, Hoenicka J, Ponce G, Rodriguez-Jimenez R, Jimenez-Arriero MA, Perez-Hernandez E, et al. (AAT)n repeat in the cannabinoid receptor gene, CNR1: association with schizophrenia in a Spanish population. Eur Arch Psychiatry Clin Neurosci 2006;256:437-441. https://doi.org/10.1007/s00406-006-0665-3
  57. Almeida B, Fernandes S, Abreu IA, Macedo-Ribeiro S. Trinucleotide repeats: a structural perspective. Front Neurol 2013;4:76.
  58. La Spada AR, Taylor JP. Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 2010;11:247-258. https://doi.org/10.1038/nrg2748
  59. McMurray CT. Mechanisms of trinucleotide repeat instability during human development. Nat Rev Genet 2010;11:786-799. https://doi.org/10.1038/nrg2828