Pharmacogenetics of tardive dyskinesia

Combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism

Bernard Lerer, Ronnen H. Segman, Heiner Fangerau, Ann K. Daly, Vincenzo S. Basile, Roberto Cavallaro, Harald N. Aschauer, Robin G. McCreadie, Stephanie Ohlraun, Nicol Ferrier, Mario Masellis, Massimiliano Verga, Joachim Scharfetter, Marcella Rietschel, Roger Lovlie, Uriel Heresco Levy, Herbert Y. Meltzer, James L. Kennedy, Vidar M. Steen, Fabio Macciardi

Research output: Contribution to journalArticle

227 Citations (Scopus)

Abstract

Variability among individuals in their therapeutic response to psychotropic drugs and in susceptibility to adverse effects is considerable. Pharmacogenetics addresses the contribution of genetic factors to this variability. An important focus of interest in pharmacogenetics has been on candidate genes that play a role in susceptibility to the antipsychotic drug-induced adverse effect, tardive dyskinesia (TD). Four published studies have reported an association between a serine (ser) to glycine (gly) polymorphism in exon 1 of the dopamine D3 receptor gene (DRD3) and TD; three failed to replicate this finding and one found an insignificant trend. We examined the association in a pooled sample of 780 patients (317 with TD and 463 without TD) drawn from 6 research centers, who were divided into 8 groups based on their population origin. The analysis employed stepwise logistic regression so as to allow confounding effects of group, age, and gender to be taken into account. TD was significantly associated with DRD3 gly allele carrier status (x2=4.46, df 1, p = .04) and with DRD3 genotype (x2=6.62, df 2, p = .04) over and above the effect of group. Similar positive effects were observed when controlling for age and gender (x2=5.02, df 1, p = .02 for gly allele carrier status; x2 = 7.51, df 2, p = .002 for genotype). Examining abnormal involuntary movement scores as a continuous variable, we found that patients homozygous for the gly allele had significantly higher scores than ser-gly heterozygotes (p = .006) or ser-ser homozygotes (p <.0001). We also performed a meta-analysis that included, besides the groups in the combined analysis, three other published studies on DRD3 and TD. The Mantel-Haenszel pooled odds ratio for DRD3 gly allele carrier status increasing susceptibility to TD was 1.33 (95% CI 1.04-1.70, p = .02); the cumulative pooled estimate showed an odds ratio of 1.52 (95% CI 1.08-1.68, p <.0001). These findings support a small but significant contribution of the DRD3 ser9gly polymorphism to TD susceptibility that is demonstrable over and above population effects and the effect of age and gender on the phenotype.

Original languageEnglish
Pages (from-to)105-119
Number of pages15
JournalNeuropsychopharmacology
Volume27
Issue number1
DOIs
Publication statusPublished - 2002

Fingerprint

Dopamine D3 Receptors
Pharmacogenetics
Glycine
Serine
Genes
Alleles
Dyskinesias
Odds Ratio
Genotype
Tardive Dyskinesia
Psychotropic Drugs
Homozygote
Heterozygote
Antipsychotic Agents
Population
Meta-Analysis
Exons
Age Groups
Logistic Models
Phenotype

Keywords

  • Antipsychotic drugs
  • Dopamine D3 receptors
  • Molecular genetics
  • Pharmacogenetics
  • Pharmacogenomics
  • Schizophrenia
  • Single nucleotide polymorphism
  • Tardive dyskinesia

ASJC Scopus subject areas

  • Pharmacology

Cite this

Pharmacogenetics of tardive dyskinesia : Combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism. / Lerer, Bernard; Segman, Ronnen H.; Fangerau, Heiner; Daly, Ann K.; Basile, Vincenzo S.; Cavallaro, Roberto; Aschauer, Harald N.; McCreadie, Robin G.; Ohlraun, Stephanie; Ferrier, Nicol; Masellis, Mario; Verga, Massimiliano; Scharfetter, Joachim; Rietschel, Marcella; Lovlie, Roger; Levy, Uriel Heresco; Meltzer, Herbert Y.; Kennedy, James L.; Steen, Vidar M.; Macciardi, Fabio.

In: Neuropsychopharmacology, Vol. 27, No. 1, 2002, p. 105-119.

Research output: Contribution to journalArticle

Lerer, B, Segman, RH, Fangerau, H, Daly, AK, Basile, VS, Cavallaro, R, Aschauer, HN, McCreadie, RG, Ohlraun, S, Ferrier, N, Masellis, M, Verga, M, Scharfetter, J, Rietschel, M, Lovlie, R, Levy, UH, Meltzer, HY, Kennedy, JL, Steen, VM & Macciardi, F 2002, 'Pharmacogenetics of tardive dyskinesia: Combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism', Neuropsychopharmacology, vol. 27, no. 1, pp. 105-119. https://doi.org/10.1016/S0893-133X(02)00293-2
Lerer, Bernard ; Segman, Ronnen H. ; Fangerau, Heiner ; Daly, Ann K. ; Basile, Vincenzo S. ; Cavallaro, Roberto ; Aschauer, Harald N. ; McCreadie, Robin G. ; Ohlraun, Stephanie ; Ferrier, Nicol ; Masellis, Mario ; Verga, Massimiliano ; Scharfetter, Joachim ; Rietschel, Marcella ; Lovlie, Roger ; Levy, Uriel Heresco ; Meltzer, Herbert Y. ; Kennedy, James L. ; Steen, Vidar M. ; Macciardi, Fabio. / Pharmacogenetics of tardive dyskinesia : Combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism. In: Neuropsychopharmacology. 2002 ; Vol. 27, No. 1. pp. 105-119.
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T2 - Combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism

AU - Lerer, Bernard

AU - Segman, Ronnen H.

AU - Fangerau, Heiner

AU - Daly, Ann K.

AU - Basile, Vincenzo S.

AU - Cavallaro, Roberto

AU - Aschauer, Harald N.

AU - McCreadie, Robin G.

AU - Ohlraun, Stephanie

AU - Ferrier, Nicol

AU - Masellis, Mario

AU - Verga, Massimiliano

AU - Scharfetter, Joachim

AU - Rietschel, Marcella

AU - Lovlie, Roger

AU - Levy, Uriel Heresco

AU - Meltzer, Herbert Y.

AU - Kennedy, James L.

AU - Steen, Vidar M.

AU - Macciardi, Fabio

PY - 2002

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N2 - Variability among individuals in their therapeutic response to psychotropic drugs and in susceptibility to adverse effects is considerable. Pharmacogenetics addresses the contribution of genetic factors to this variability. An important focus of interest in pharmacogenetics has been on candidate genes that play a role in susceptibility to the antipsychotic drug-induced adverse effect, tardive dyskinesia (TD). Four published studies have reported an association between a serine (ser) to glycine (gly) polymorphism in exon 1 of the dopamine D3 receptor gene (DRD3) and TD; three failed to replicate this finding and one found an insignificant trend. We examined the association in a pooled sample of 780 patients (317 with TD and 463 without TD) drawn from 6 research centers, who were divided into 8 groups based on their population origin. The analysis employed stepwise logistic regression so as to allow confounding effects of group, age, and gender to be taken into account. TD was significantly associated with DRD3 gly allele carrier status (x2=4.46, df 1, p = .04) and with DRD3 genotype (x2=6.62, df 2, p = .04) over and above the effect of group. Similar positive effects were observed when controlling for age and gender (x2=5.02, df 1, p = .02 for gly allele carrier status; x2 = 7.51, df 2, p = .002 for genotype). Examining abnormal involuntary movement scores as a continuous variable, we found that patients homozygous for the gly allele had significantly higher scores than ser-gly heterozygotes (p = .006) or ser-ser homozygotes (p <.0001). We also performed a meta-analysis that included, besides the groups in the combined analysis, three other published studies on DRD3 and TD. The Mantel-Haenszel pooled odds ratio for DRD3 gly allele carrier status increasing susceptibility to TD was 1.33 (95% CI 1.04-1.70, p = .02); the cumulative pooled estimate showed an odds ratio of 1.52 (95% CI 1.08-1.68, p <.0001). These findings support a small but significant contribution of the DRD3 ser9gly polymorphism to TD susceptibility that is demonstrable over and above population effects and the effect of age and gender on the phenotype.

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