Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism

The Pharmacogenomics Journal volume 5, pages 60–69 (2005)Cite this article

Abstract

Understanding the pharmacogenetic basis of developing iatrogenic disorders such as Tardive Dyskinesia (TD) has significant clinical implications. CYP1A2, an inducible gene of the cytochrome P450 family of genes, has been suggested to contribute to the metabolism of typical antipsychotics in subjects with schizophrenia on long-term treatment, and has been considered as a potential candidate gene for development of TD. In this study, we have investigated the significance of CYP1A2 gene polymorphisms in TD susceptibility among chronic schizophrenia sufferers (n=335) from north India. TD was diagnosed in ∼29% (96/335) of these subjects. Of the 96 TD positives, 28 had been treated with typical antipsychotics alone, 23 with atypical antipsychotics alone and 45 patients had received both classes of drugs during the course of their illness. Out of the six SNPs tested, CYP1A2*2, *4, *5, *6 were found to be monomorphic in our population. CYP1A2*1C and CYP1A2*1F were polymorphic and were analyzed in the study sample. Since these two allelic variants lead to lesser inducibility among smokers, the smoking status of TD patients was also considered for all subsequent analysis. We observed increased severity of TD among TD-Y smokers, who were carriers of CYP1A2*1C (G>A) variant allele and had received only typical antipsychotic drugs (F(1,8)=9.203, P=0.016). No significant association of CYP1A2*1F with TD was observed irrespective of the class of drug they received or their smoking status. However, we found a significant association of CYP1A2*1F with schizophrenia (χ2=6.572, df=2, P=0.037).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Yassa R, Ananth J . Familial Tardive dyskinesia. Am J Psychiatry 1981; 138: 1618–1619.

    Article  CAS  PubMed  Google Scholar 

  2. 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 

  3. Kane JM, Smith JM . Tardive Dyskinesia: prevalence and risk factors 1959 to 1979. Arch Gen Pscychiaty 1982; 39: 473–481.

    Article  CAS  Google Scholar 

  4. Bergen J, Kitchin R, Berry G . Predictors of the course of Tardive Dyskinesia in patients receiving neuroleptics. Biol Psychiatry 1992; 32: 580–594.

    Article  CAS  PubMed  Google Scholar 

  5. Jeste DW, Wyatt RJ . Dogma disputed: is tardive dyskinesia due to postsynaptic dopamine receptor sensitivity? J Clin Psychiatry 1981; 42: 455–457.

    CAS  PubMed  Google Scholar 

  6. Casey DE, Geralch J, Bjondal N . Levodopa and receptor sensitivity modification in tardive dyskinesia. Psychopharmacology 1982; 78: 89–92.

    Article  CAS  PubMed  Google Scholar 

  7. Geralch J, Casey DE . Sulpiride in tardive dyskinesia. Acta Psychiatr Scand 1984; 311: 93–102.

    Article  Google Scholar 

  8. Mehsul CK, Casey DE . Regional, reversible ultrastructural changesin rat brain with chronic neuroleptic treatment. Brain Res 1989; 489: 338–346.

    Article  Google Scholar 

  9. Gordon JH, Fields JZ . A permanent dopamine receptor upregulation in the ovariectomized rat. Pharmacol Biochem Behav 1989; 33: 123–125.

    Article  CAS  PubMed  Google Scholar 

  10. Basile VS, Masellis M, Potkin SG, Kennedy JL . Pharmacogenomics in schizophrenia: the quest for individualized therapy. Hum Mol Genet 2002; 11: 2517–2530.

    Article  CAS  PubMed  Google Scholar 

  11. Lerer B, Segman RH, Fangerau H, Daly AK, Basile VS, Cavallaro R et al. Pharmacogenetics of Tardive Dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism. Neuropsychopharmacology 2002; 27: 105–118.

    Article  CAS  PubMed  Google Scholar 

  12. Shimada T, Yamazaki H, Mimura M, Inui Y, Gungerich FP . Interindividual variations in human liver cytochrome P450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Ther 1994; 270: 414–423.

    CAS  Google Scholar 

  13. Arthur H, Dahl ML, Siwers B, Sjoqvist F . Polymorphic drug metabolism in schizophrenia patients with tardive dyskinesia. J Clin Psychpharmacol 1995; 15: 211–216.

    Article  CAS  Google Scholar 

  14. Armstrong M, Daly AK, Blennerhassett R, Ferrier N, Idle JR . Antipsychotic induced movement disorders in schizophrenics in relation to CYP2D6 genotype. Br J Psychiatry 1997; 170: 23–26.

    Article  CAS  PubMed  Google Scholar 

  15. Basile VS, Ozdemir V, Masellis M, Walker ML, Meltzer HY, Lieberman JA et al. A functional polymorphism of the cytochrome P450 1A2(CYP1A2) gene: association with tardive dyskinesia in schizophrenia. Mol Psychiatry 2000; 5: 410–417.

    Article  CAS  PubMed  Google Scholar 

  16. Smith SS, Fiore MC . The epidemiology of tobacco use, dependence and cessation in the United States. Primary Care 1999; 26: 433–461.

    Article  CAS  PubMed  Google Scholar 

  17. Nakajima M, Yokoi T, Mizutani M, Kinoshita M, Funayama M, Kamakati T . Genetic polymorphism in the 5′-flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans. J Biochem 1999; 125: 803–808.

    Article  CAS  PubMed  Google Scholar 

  18. Sachse C, Brockmoller J, Bauer S, Roots I . Functional significance of a C>A polymorphism in intron I of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol 1999; 47: 445–449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Guy W (ed). Early Clinical Drug Evaluation Unit b Assessment Manual. US Department of health and human services, National Institute of Mental Health (NIMH): Rockville, Maryland 1976.

  20. Schultze TG, Schumacher J, Muller DJ, Krauss H, Alfter D, Maroldt A et al. Lack of association between a functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene and tardive dyskinesia in schizophrenia. Am J Med Genet 2001; 105: 498–501.

    Article  Google Scholar 

  21. Chong S, Tan E, Tan CH, Mythily . Smoking and Tardive Dyskinesia: lack of involvement of the CYP1A2 gene. J Psychiatry Neurosci 2003; 28: 185–189.

    PubMed  PubMed Central  Google Scholar 

  22. 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 

  23. Kane JM . Clinical efficacy of clozapine in treatment-refractory schizophrenia: an overview. Br J Psychiatry 1992; 160: 41–45.

    Article  Google Scholar 

  24. Yassa R, Jeste DV . Gender differences in tardive dyskinesia: a critical review of the literature. Schizophr Bull 1992; 18: 701–715.

    Article  CAS  PubMed  Google Scholar 

  25. Chevalier D, Cauffiez C, Allorge D, Lo-Guidice JM, Lhermitte M, Lafitte JJ et al. Five novel natural allelic variants – 951 A>C, 1042 G>A (D348N), 1156A>T (I386F), 1217 G>A (C406Y) and 1291 C>T (C4341Y) – of the mutation in a French Caucasian population. Hum Mutat 2001; 17: 355–360.

    PubMed  Google Scholar 

  26. Nebert DW . Polymorphism in drug metabolizing enzymes: what is their clinical relevance and why do they exists? Am J Hum Genet 1997; 60: 265–271.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ikeya K, Jaiswal AK, Owens RA, Jones JE, Nebert DW, Kimura S . Human CYP1A2: sequence, gene structure, comparison with mouse and rat orthologous gene, and differences in liver mRNA expression. Mol Endocrinol 1989; 3: 1399–1408.

    Article  CAS  PubMed  Google Scholar 

  28. Pickwell GV, Shih H, Quattrochi LC . Interaction of upstream stimulatory factor proteins with an E-box located within the human CYP1A2 5′-flanking gene contributes to basal transcriptional gene activation. Biochem Pharmacol 2003; 65: 1087–1096.

    Article  CAS  PubMed  Google Scholar 

  29. Hamdy SI, Hiratsuka M, Narahara K, Endo N, El-Enany M, Moursi N et al. Genotyping of four genetic polymorphisms in the CYP1A2 gene in the Egyptian population. Br J Clin Pharmacol 2003; 55: 321–324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Coon H, Jensen S, Holik J, Hoff M, Myles-Worsley M, Reimherr F et al. Genomic scan for genes predisposing to schizophrenia. Am J Med Genet 1994; 54: 59–71.

    Article  CAS  PubMed  Google Scholar 

  31. Kaufman CA, Suarez B, Malaspina D, Pepel J, Svarakic D, Meyer J et al. NIMH genetics initiative millenium schizophrenia consortium: linkage analysis of African American pedigrees. Am J Med Genet 1998; 88: 29–33.

    Google Scholar 

  32. Stober G, Saar K, Ruschendorf F, Meyer J, Nurnberg G, Jatzke S et al. Splitting schizophrenia: periodic catatonia - susceptibility locus on chromosome 15q15. Am J Hum Genet 2000; 67: 1201–1207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Freedman A, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. PNAS 1997; 94: 587–592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Riley B P, Makoff A, Mogudi-Carter M, Jenkins T, Williamson RD, Murray R . Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern Africal Bantu families. Am J Med Genet 2000; 96: 196–201.

    Article  PubMed  Google Scholar 

  35. Liu C, Hwo H, Lin M, Ou-yang W, Lee S, Fann C et al. Suggestive evidence for linkage of schizophrenia markers at chromosome 15q13–14 in Taiwanese families. Am J Med Genet 2000; 105: 658–661.

    Article  Google Scholar 

  36. Morse DC, Steim AP, Thomas PE, Lowndess HE . Distribution and induction of cytochrome P450 1A1 and 1A2 in rat brain. Toxicol Appl Pharmacol 1998; 152: 232–239.

    Article  CAS  PubMed  Google Scholar 

  37. Nurnberger Jr JI, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J et al. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry 1994; 5: 849–859.

    Article  Google Scholar 

  38. Deshpande SN, Mathur MNL, Das SK, Bhatia T, Sharma SD, Nimgaonkar VL . A hindi version of the diagnostic interview for genetic studies. Schizophr Bull 1998; 24: 489–493.

    Article  CAS  PubMed  Google Scholar 

  39. Schooler NR, Kane JM . Research diagnoses for tardive Dyskinesia. Arch Gen Prychiatry 1982; 39: 486–487.

    CAS  Google Scholar 

  40. Simpson GM, Angus JWS . Drug-induced extrapyramidal disorder – a rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970; 212: 20–27.

    Article  CAS  PubMed  Google Scholar 

  41. Sambrook J, Fritsch EE, Maniatis T . Molecular Cloning: A Laboratory Manual. 2nd edn, Cold Spring Harbor Laboratory press: Cold Spring Harbor, NY 1989.

  42. Gordon D, Finch SJ, Nothnagel M, Ott J . Power and sample size calculations for case–control genetic association tests when errors present: application to single nucleotide polymorphisms. Hum Heredity 2002; 54: 22–33.

    Article  PubMed  Google Scholar 

  43. Gordon D, Levenstien MA, Finch SJ, Ott J . Errors and linkage disequilibrium interact multiplicatively when computing sample sizes for genetic case–control association studies. Pacific Symposium on Biocomputing. 2003, pp 490–501.

  44. Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Stephens M, Donnelly P . Comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162–1169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sham PC, Curtis D . Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 1995; 59: 97–105.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work is supported by Indo-Israel grants BT/IC-2/Israel/Deshpande/2002 and BT/IC-2/00/Smita/99 (to SND, BKT, BL); Department of Biotechnology (Govt of India) Grant BT/PR2425/Med 13/089/2001 (to BKT and SND); Indo-US Grant N-443-645 (to VLN, BKT, SND); and a research fellowship from the University Grants Commission, New Delhi to AKT.

Author information

Authors and Affiliations

  1. Department of Genetics, University of Delhi South Campus, New Delhi, India

    A K Tiwari & B K Thelma

  2. Department of Psychiatry, Dr RML Hospital, New Delhi, India

    S N Deshpande

  3. Indo-US Project on Schizophrenia Genetics, New Delhi, India

    S N Deshpande, T Bhatia, S R Mukit, V Shriharsh, V L Nimagaonkar & B K Thelma

  4. Biometrics Division, Indian Agricultural Statistics Research Institute, New Delhi, India

    A R Rao

  5. Department of Psychiatry, Hadassah-Hebrew University Medical Center, Ein Karem, Jerusalem, Israel

    B Lerer

  6. Department of Psychiatry, University of Pittsburgh, PA, USA

    V L Nimagaonkar

Authors
  1. A K Tiwari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S N Deshpande
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A R Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Bhatia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S R Mukit
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. V Shriharsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B Lerer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. V L Nimagaonkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. B K Thelma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B K Thelma.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tiwari, A., Deshpande, S., Rao, A. et al. Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism. Pharmacogenomics J 5, 60–69 (2005). https://doi.org/10.1038/sj.tpj.6500282

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500282

Keywords

This article is cited by

Search

Advanced search

Quick links