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Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant

The Pharmacogenomics Journal volume 10, pages 200–218 (2010)Cite this article

Abstract

D2 blockade has been implicated in having a central role in antipsychotic response. However, treatment refractoriness, in spite of complete D2 blockade, as well as the efficacy of clozapine (CLZ) in a portion of this patient population, indicates the involvement of other factors as well. Several lines of evidence suggest a role for D3. Furthermore, an earlier meta-analysis by Jönsson et al. (2003) (n=233) suggested a role for genetic variation in the D3 gene. Relevant to this study, Jönsson et al. found the Ser allele of the D3 serine-to-glycine substitution at amino acid position 9 (Ser9Gly) polymorphism to be associated with worse CLZ response compared with the Gly allele. In this study, we attempt to validate these findings by performing a meta-analysis in a much larger sample (n=758). Eight other variants were also tested in our own sample to explore the possible effect of other regions of the gene. We report a negative but consistent trend across individual studies in our meta-analysis for the DRD3 Ser allele and poor CLZ response. A possible minor role for this single-nucleotide polymorphism cannot be disregarded, as our sample size may have been insufficient. Other DRD3 variants and haplotypes of possible interest were also identified for replication in future studies.

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Acknowledgements

RH was supported by the Canadian Institute of the Health Research (CIHR) Molecular Medicine Training Program, JLK was supported by the CIHR and GlaxoSmithKline, and AM was supported by the Instituto de Salud Carlos III, Centro de Investigacion en Red de Salud Mental, CIBERSAM.

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Authors and Affiliations

  1. Neurogenetics Section, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada

    R Hwang, C Zai, A Tiwari, D J Müller & J L Kennedy

  2. Department of Psychological Medicine, King's College London, Institute of Psychiatry, Denmark Hill, London, UK,

    M J Arranz & J Munro

  3. Division of Neuroscience and Mental Health, Department of Cellular and Molecular Neuroscience, Neurogenetics Group, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK

    A G Morris

  4. Benito Menni Complex Assitencial en Salut Mental, Germanes Hospitalàries del Sagrat Cor de Jesús, Sant Boi de Llogregat, Barcelona, Spain

    P J McKenna

  5. Brain Imaging Center, University of California, Irvine, Irvine, CA, USA

    S G Potkin

  6. University of North Carolina Medical School, Neurosciences Hospital, Chapel, Hill, NC, USA

    J A Lieberman

  7. Psychiatric Hospital at Vanderbilt University, Nashville, TN, USA

    H Y Meltzer

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JLK has been a consultant for GlaxoSmithKline, Johnson and Johnson and for TheraGenetics. JLK and RH are co-authors on a patent application for genetic prediction of antipsychotic response.

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Hwang, R., Zai, C., Tiwari, A. et al. Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant. Pharmacogenomics J 10, 200–218 (2010). https://doi.org/10.1038/tpj.2009.65

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