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: V. Association of CYP1A2 1545 C>T polymorphism

The Pharmacogenomics Journal volume 7, pages 305–311 (2007)Cite this article

Abstract

Tardive dyskinesia (TD) is an iatrogenic disorder observed in ∼20–30% of schizophrenia patients on long-term treatment with typical antipsychotic drugs. CYP1A2 is involved in the metabolism of atypical antipsychotic drugs such as clozapine and olanzapine. It is not directly involved in the metabolism of typical antipsychotic drugs, but gains importance when the schizophrenia patients are under long-term chronic treatment, acting as a low-affinity high-capacity metabolizing enzyme. In this study, we have completely sequenced the coding region to ascertain the presence of common coding polymorphisms and their role if any in susceptibility to TD and schizophrenia. Four previously reported polymorphisms, CYP1A2*1F (intron A), rs2472304 & rs3743484 (intron D) and rs2470890 (CYP1A2 1545 C>T) in exon 7 were identified. We further investigated whether the CYP1A2 1545 C>T polymorphism has any role to play in susceptibility to TD and in schizophrenia per se. Association of this single nucleotide polymorphism with TD (P=0.03) and schizophrenia (P=0.04) was observed, but was rendered insignificant after corrections for multiple comparisons.

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

Figure 1

Similar content being viewed by others

References

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

    Article  CAS  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  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  Google Scholar 

  5. Andreassen OA, Jorgensen HA . Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia? Prog Neurobiol 2000; 61: 525–541.

    Article  CAS  Google Scholar 

  6. Lohr JB, Kuczenski R, Niculescu AB . Oxidative mechanisms and tardive dyskinesia. CNS Drugs 2003; 17: 47–62.

    Article  CAS  Google Scholar 

  7. Casey DE . Pathophysiology of antipsychotic drug-induced movement disorders. J Clin Psychiatry 2004; 65 (Suppl 9): 25–28.

    CAS  PubMed  Google Scholar 

  8. 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  Google Scholar 

  9. 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  Google Scholar 

  10. 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 

  11. 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  Google Scholar 

  12. 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  Google Scholar 

  13. 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  Google Scholar 

  14. Tiwari AK, Deshpande SN, Rao AR, Bhatia T, Mukit SR, Shriharsh V et al. Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism. Pharmacogenomics J 2005; 5: 60–69.

    Article  CAS  Google Scholar 

  15. 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  Google Scholar 

  16. Chevalier D, Cauffiez C, Allorge D, Lo-Guidice JM, Lhermitte M, Lafitte JJ et al. Five novel natural allelic variants – 951 A4C, 1042 G4A (D348N), 1156A4T (I386F), 1217 G4A (C406Y) and 1291 C4T (C4341Y) – of the mutation in a French Caucasian population. Hum Mutat 2001; 17: 355–360.

    PubMed  Google Scholar 

  17. Dolder CR, Jeste DV . Incidence of tardive dyskinesia with typical versus atypical antipsychotics in very high risk patients. Biol Psychiatry 2003; 53: 1142–1145.

    Article  CAS  Google Scholar 

  18. Ossowska K . Neuronal basis of neuroleptic-induced extrapyramidal side effects. Pol J Pharmacol 2002; 54: 299–312.

    Article  CAS  Google Scholar 

  19. Prior TI, Baker GB . Interactions between the cytochrome P450 system and the second-generation antipsychotics. J Psychiatry Neurosci 2003; 28: 99–112.

    PubMed  PubMed Central  Google Scholar 

  20. 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  Google Scholar 

  21. 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. Proc Natl Acad Sci USA 1997; 94: 587–592.

    Article  CAS  Google Scholar 

  22. 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 

  23. 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  Google Scholar 

  24. 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  Google Scholar 

  25. 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, MD, 1976.

    Google Scholar 

  26. 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  Google Scholar 

  27. 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  Google Scholar 

  28. 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  Google Scholar 

Download references

Acknowledgements

This work is supported by a Department of Biotechnology (Government of India) Grant BT/PR2425/Med 13/089/2001 (to BKT and SND); Indo-Israel Grants BT/IC-2/Israel/Deshpande/2002 and BT/IC-2/00/Smita/99 (to SND, BKT, BL); a grant from NIMH to VLN (MH5624) and a senior 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. Department of Psychiatry, Hadassah-Hebrew University Medical Center, Ein Karem, Jerusalem, Israel

    B Lerer

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

    V L Nimgaonkar

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. B Lerer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V L Nimgaonkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B K Thelma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B K Thelma.

Additional information

Duality of Interest

The authors declare that they have no competing financial interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tiwari, A., Deshpande, S., Lerer, B. et al. Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C>T polymorphism. Pharmacogenomics J 7, 305–311 (2007). https://doi.org/10.1038/sj.tpj.6500415

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500415

Keywords

This article is cited by

Search

Advanced search

Quick links