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Association study of Cannabinoid receptor 1 (CNR1) gene in tardive dyskinesia

The Pharmacogenomics Journal volume 12, pages 260–266 (2012)Cite this article

Abstract

Tardive dyskinesia (TD) is a severe, debilitating movement disorder observed in 25–30% of the patients treated with typical antipsychotics. Cannabinoid receptor 1 (CNR1) activators tend to inhibit movement, an effect prevented by rimonabant and other selective CNR1 antagonists. Furthermore, CNR1 receptor is downregulated in Huntington's disease and upregulated in Parkinson's disease. Twenty tagSNPs spanning the CNR1 gene were analyzed in schizophrenia patients of European ancestry (n=191; 74 with TD). Significant genotypic (P=0.012) and allelic (P=0.012) association was observed with rs806374 (T>C). Carriers of the CC genotype were more likely to be TD positive (CC vs TT+TC, odds ratio=3.4 (1.5–7.8), P=0.003) and had more severe TD (CC vs TT+TC; 9.52±9.2 vs 5.62±6.9, P=0.046). These results indicate a possible role of CNR1 in the development of TD in our patient population. However, these observations are marginal after correcting for multiple testing and need to be replicated in a larger patient population.

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References

  1. Casey DE . Neuroleptic drug-induced extrapyramidal syndromes and tardive dyskinesia. Schizophr Res 1991; 4: 109–120.

    Article  CAS  PubMed  Google Scholar 

  2. Leucht S, Wahlbeck K, Hamann J, Kissling W . New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet 2003; 361: 1581–1589.

    Article  CAS  PubMed  Google Scholar 

  3. Miller DD, Caroff SN, Davis SM, Rosenheck RA, McEvoy JP, Saltz BL et al. Extrapyramidal side-effects of antipsychotics in a randomised trial. Br J Psychiatry 2008; 193: 279–288.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Correll CU, Schenk EM . Tardive dyskinesia and new antipsychotics. Curr Opin Psychiatry 2008; 21: 151–156.

    Article  PubMed  Google Scholar 

  5. Tarsy D, Baldessarini RJ . Epidemiology of tardive dyskinesia: is risk declining with modern antipsychotics? Mov Disord 2006; 21: 589–598.

    Article  PubMed  Google Scholar 

  6. Gerlach J . Improving outcome in schizophrenia: the potential importance of EPS and neuroleptic dysphoria. Ann Clin Psychiatry 2002; 14: 47–57.

    Article  PubMed  Google Scholar 

  7. Marsalek M . Tardive drug-induced extrapyramidal syndromes. Pharmacopsychiatry 2000; 33 (Suppl 1): 14–33.

    Article  CAS  PubMed  Google Scholar 

  8. Muller DJ, Schulze TG, Knapp M, Held T, Krauss H, Weber T et al. Familial occurrence of tardive dyskinesia. Acta Psychiatr Scand 2001; 104: 375–379.

    Article  CAS  PubMed  Google Scholar 

  9. Muller DJ, Shinkai T, De Luca V, Kennedy JL . Clinical implications of pharmacogenomics for tardive dyskinesia. Pharmacogenomics J 2004; 4: 77–87.

    Article  CAS  PubMed  Google Scholar 

  10. Thelma B, Srivastava V, Tiwari AK . Genetic underpinnings of tardive dyskinesia: passing the baton to pharmacogenetics. Pharmacogenomics 2008; 9: 1285–1306.

    Article  CAS  PubMed  Google Scholar 

  11. Katona I, Freund TF . Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med 2008; 14: 923–930.

    Article  CAS  PubMed  Google Scholar 

  12. Hudson BD, Hebert TE, Kelly ME . Ligand- and heterodimer-directed signaling of the CB(1) cannabinoid receptor. Mol Pharmacol 2010; 77: 1–9.

    Article  CAS  PubMed  Google Scholar 

  13. van der Stelt M, Di Marzo V . The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: implications for neurological and psychiatric disorders. Eur J Pharmacol 2003; 480: 133–150.

    Article  CAS  PubMed  Google Scholar 

  14. Matyas F, Yanovsky Y, Mackie K, Kelsch W, Misgeld U, Freund TF . Subcellular localization of type 1 cannabinoid receptors in the rat basal ganglia. Neuroscience 2006; 137: 337–361.

    Article  CAS  PubMed  Google Scholar 

  15. Fernandez-Ruiz J . The endocannabinoid system as a target for the treatment of motor dysfunction. Br J Pharmacol 2009; 156: 1029–1040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Albin RL, Young AB, Penney JB . The functional anatomy of basal ganglia disorders. Trends Neurosci 1989; 12: 366–375.

    Article  CAS  PubMed  Google Scholar 

  17. Surmeier DJ, Ding J, Day M, Wang Z, Shen W . D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci 2007; 30: 228–235.

    Article  CAS  PubMed  Google Scholar 

  18. Kreitzer AC, Malenka RC . Striatal plasticity and basal ganglia circuit function. Neuron 2008; 60: 543–554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI . Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci USA 1999; 96: 5780–5785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Martin AB, Fernandez-Espejo E, Ferrer B, Gorriti MA, Bilbao A, Navarro M et al. Expression and function of CB1 receptor in the rat striatum: localization and effects on D1 and D2 dopamine receptor-mediated motor behaviors. Neuropsychopharmacology 2008; 33: 1667–1679.

    Article  CAS  PubMed  Google Scholar 

  21. Rodriguez de Fonseca F, Del Arco I, Martin-Calderon JL, Gorriti MA, Navarro M . Role of the endogenous cannabinoid system in the regulation of motor activity. Neurobiol Dis 1998; 5 (6 Part B): 483–501.

    Article  CAS  PubMed  Google Scholar 

  22. Giuffrida A, Parsons LH, Kerr TM, Rodriguez de Fonseca F, Navarro M, Piomelli D . Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci 1999; 2: 358–363.

    Article  CAS  PubMed  Google Scholar 

  23. Kreitzer AC, Malenka RC . Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models. Nature 2007; 445: 643–647.

    Article  CAS  PubMed  Google Scholar 

  24. Shen W, Flajolet M, Greengard P, Surmeier DJ . Dichotomous dopaminergic control of striatal synaptic plasticity. Science 2008; 321: 848–851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zai CC, Hwang RW, De Luca V, Muller DJ, King N, Zai GC et al. Association study of tardive dyskinesia and twelve DRD2 polymorphisms in schizophrenia patients. Int J Neuropsychopharmacol 2007; 10: 639–651.

    Article  CAS  PubMed  Google Scholar 

  26. Zai CC, Romano-Silva MA, Hwang R, Zai GC, Deluca V, Muller DJ et al. Genetic study of eight AKT1 gene polymorphisms and their interaction with DRD2 gene polymorphisms in tardive dyskinesia. Schizophr Res 2008; 106: 248–252.

    Article  PubMed  Google Scholar 

  27. Zai CC, Tiwari AK, De Luca V, Muller DJ, Bulgin N, Hwang R et al. Genetic study of BDNF, DRD3, and their interaction in tardive dyskinesia. Eur Neuropsychopharmacol 2009; 19: 317–328.

    Article  CAS  PubMed  Google Scholar 

  28. Zai CC, Tiwari AK, Basile V, de Luca V, Muller DJ, Voineskos AN et al. Oxidative stress in tardive dyskinesia: genetic association study and meta-analysis of NADPH quinine oxidoreductase 1 (NQO1) and superoxide dismutase 2 (SOD2, MnSOD) genes. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 50–56.

    Article  CAS  PubMed  Google Scholar 

  29. Guy W . ECDEU Assessment Manual for Psychopharmacology (revised edn.) Department of Health, Education and Welfare: Washington, DC, 1976.

    Google Scholar 

  30. Schooler NR, Kane JM . Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry 1982; 39: 486–487.

    CAS  PubMed  Google Scholar 

  31. Basile VS, Masellis M, Badri F, Paterson AD, Meltzer HY, Lieberman JA et al. Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia. Neuropsychopharmacology 1999; 21: 17–27.

    Article  CAS  PubMed  Google Scholar 

  32. Lieberman J, Kane JM, Woerner M, Weinhold P, Basavaraju N, Kurucz J et al. Prevalence of tardive dyskinesia in elderly samples. Psychopharmacol Bull 1984; 20: 382–386.

    CAS  PubMed  Google Scholar 

  33. Lieberman J, Johns C, Cooper T, Pollack S, Kane J . Clozapine pharmacology and tardive dyskinesia. Psychopharmacology (Berl) 1989; 99 (Suppl): S54–S59.

    Article  Google Scholar 

  34. Lahiri DK, Nurnberger Jr JI . A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 1991; 19: 5444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121.

    Article  PubMed  Google Scholar 

  36. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  PubMed  Google Scholar 

  37. Gauderman WJ, Morrison JM . QUANTO 1.1: a computer program for power and sample size calculations for genetic-epidemiology studies, http://hydra.usc.edu/gxe, 2006.

  38. Tiwari AK, Zai CC, Likhodi O, Lisker A, Singh D, Souza RP, et al. A common polymorphism in the cannabinoid receptor 1 (CNR1) gene is associated with antipsychotic-induced weight gain in Schizophrenia. Neuropsychopharmacology 2010; 35: 1315–1324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nyholt DR . A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 2004; 74: 765–769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li J, Ji L . Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity 2005; 95: 221–227.

    Article  CAS  PubMed  Google Scholar 

  41. Zhang PW, Ishiguro H, Ohtsuki T, Hess J, Carillo F, Walther D et al. Human cannabinoid receptor 1: 5′ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Mol Psychiatry 2004; 9: 916–931.

    Article  CAS  PubMed  Google Scholar 

  42. Pabst O, Forster R, Lipp M, Engel H, Arnold HH . NKX2.3 is required for MAdCAM-1 expression and homing of lymphocytes in spleen and mucosa-associated lymphoid tissue. EMBO J 2000; 19: 2015–2023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet 2008; 40: 710–712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Franke A, Balschun T, Karlsen TH, Hedderich J, May S, Lu T et al. Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet 2008; 40: 713–715.

    Article  CAS  PubMed  Google Scholar 

  45. Van Limbergen J, Wilson DC, Satsangi J . The genetics of Crohn's disease. Annu Rev Genomics Hum Genet 2009; 10: 89–116.

    Article  CAS  PubMed  Google Scholar 

  46. Andersen B, Schonemann MD, Pearse II RV, Jenne K, Sugarman J, Rosenfeld MG . Brn-5 is a divergent POU domain factor highly expressed in layer IV of the neocortex. J Biol Chem 1993; 268: 23390–23398.

    CAS  PubMed  Google Scholar 

  47. Hayashida T, Takahashi F, Chiba N, Brachtel E, Takahashi M, Godin-Heymann N et al. HOXB9, a gene overexpressed in breast cancer, promotes tumorigenicity and lung metastasis. Proc Natl Acad Sci USA 2010; 107: 1100–1105.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Canadian Institutes of Health Research (CIHR) operating grants to JLK and DJM; a NARSAD Young Investigator Award to DJM, MH41468, the Prentiss Foundation, Ritter Foundation, Hintz family and the Peterson Family to HYM; The Bebensee Foundation fellowship to CCZ and CIHR postdoctoral fellowship to AKT.

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Authors and Affiliations

  1. Neuroscience Department, Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    A K Tiwari, C C Zai, O Likhodi, A N Voineskos, G Remington, D J Müller & J L Kennedy

  2. Psychiatric Hospital, Vanderbilt University, Nashville, TN, USA

    H Y Meltzer

  3. Department of Psychiatry, College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York City, NY, USA

    J A Lieberman

  4. Brain Imaging Center, Irvine Hall, University of California, Irvine, CA, USA

    S G Potkin

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  1. A K Tiwari
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Correspondence to J L Kennedy.

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Competing interests

AKT/CCZ/DJM: report no competing interests. HYM has received grants or is a consultant to Abbott Labs, ACADIA, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, Astra Zeneca, Glaxo Smith Kline, Memory, Cephalon, Minster, Aryx and BiolineRx. HYM is a shareholder of ACADIA. JAL reports that he serves on the Advisory Board of Bioline, GlaxoSmithKline, Intracellular Therapies, Eli Lilly, Pierre Fabre, Psychogenics and Wyeth. He does not receive financial compensation or salary support for his participation as an advisor. He receives grant support from Allon, Forest Labs, Merck and Pfizer; he holds a patent from Repligen. JLK has been a consultant to GSK, Sanofi-Aventis and Dainippon-Sumitomo.

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Tiwari, A., Zai, C., Likhodi, O. et al. Association study of Cannabinoid receptor 1 (CNR1) gene in tardive dyskinesia. Pharmacogenomics J 12, 260–266 (2012). https://doi.org/10.1038/tpj.2010.93

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