The catechol-O-methyl-transferase gene in tardive dyskinesia

Clement C. Zai; Arun K. Tiwari; Daniel J. Müller; Vincenzo De Luca; Takahiro Shinkai; Sajid Shaikh; Xingqun Ni; David Sibony; Aristotle N. Voineskos; Herbert Y. Meltzer; Jeffrey A. Lieberman; Steven G. Potkin; Gary Remington; James L. Kennedy

doi:10.3109/15622975.2010.486043

The catechol-O-methyl-transferase gene in tardive dyskinesia

Clement C. Zai, Arun K. Tiwari, Daniel J. Müller, Vincenzo De Luca, Takahiro Shinkai, Sajid Shaikh, Xingqun Ni, David Sibony, Aristotle N. Voineskos, Herbert Y. Meltzer, Jeffrey A. Lieberman, Steven G. Potkin, Gary Remington, James L. Kennedy

Psychiatry and Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

Tardive dyskinesia (TD) is a severe and potentially irreversible motor side effect linked to long-term antipsychotic exposure. Changes in dopamine neurotransmission have been implicated in the etiology of TD, and catechol-O-methyl-transferase (COMT) is an enzyme that metabolizes dopamine. Objectives. We investigated five single-nucleotide polymorphisms in addition to the functional Val158Met variant spanning the COMT gene for association with TD. Methods. We analyzed the six COMT single-nucleotide polymorphisms in a sample of schizophrenia/schizoaffective disorder patients (n=226; 196 Caucasians and 30 African Americans). Results. We found a significant association between the marker rs165599 in the 3′ untranslated region of COMT and TD (AA versus G-carrier: OR_AA2.22, 95% CI:1.234.03; P=0.007). The association appeared to be originating from males. We did not find a significant association of the other five tested polymorphisms with TD in our samples. We performed a sex-stratified meta-analysis across all of the published studies (n6 plus our own data) of COMT and TD, and found an association between ValVal genotype and TD in females (OR_ValVal1.63, 95% CI: 1.092.45; P=0.019) but not in males. Conclusions. Overall, our results suggest that the COMT gene may have a minor but consistent role in TD, although sex-stratified studies with additional markers in larger clinical samples should be performed.

Original language	English (US)
Pages (from-to)	803-812
Number of pages	10
Journal	World Journal of Biological Psychiatry
Volume	11
Issue number	6
DOIs	https://doi.org/10.3109/15622975.2010.486043
State	Published - Sep 2010

Funding

AKT, DJM, VdL, TS, SS; XN, DS, ANV, GR report no competing interests. CCZ and JLK: patent application for “ marker for tardive dyskinesia” . HYM has received grants and/or has been a consultant to: Abbott Labs, ACADIA, Eli Lilly, Janssen, Pfizer, Wyeth, Schering Plough, SureGene, Novartis, Azur, Biovail, Lundbeck, Roche, Otsuka, Dainippon Sumitomo, Cephalon, Minster, Bristol Myers Squibb, Astra Zeneca, Glaxo-Smith-Kline, Memory, 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; and he holds a patent from Repligen. JLK has been a consultant to GSK, Sanofi-Aventis, Dainippon-Sumitomo. We thank the authors of the papers included in the meta-analysis for providing genotype information for their samples. We also thank the Canadian Institute for Health Research – postdoctoral fellowship to AKT; 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, as well as the Bebensee Foundation to CCZ. We further thank the participants in the study.

Keywords

COMT
Meta-analysis
Pharmacogenetics
Schizophrenia
Tardive dyskinesia

ASJC Scopus subject areas

Psychiatry and Mental health
Biological Psychiatry

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10.3109/15622975.2010.486043

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Zai, C. C., Tiwari, A. K., Müller, D. J., De Luca, V., Shinkai, T., Shaikh, S., Ni, X., Sibony, D., Voineskos, A. N., Meltzer, H. Y., Lieberman, J. A., Potkin, S. G., Remington, G., & Kennedy, J. L. (2010). The catechol-O-methyl-transferase gene in tardive dyskinesia. World Journal of Biological Psychiatry, 11(6), 803-812. https://doi.org/10.3109/15622975.2010.486043

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title = "The catechol-O-methyl-transferase gene in tardive dyskinesia",

abstract = "Tardive dyskinesia (TD) is a severe and potentially irreversible motor side effect linked to long-term antipsychotic exposure. Changes in dopamine neurotransmission have been implicated in the etiology of TD, and catechol-O-methyl-transferase (COMT) is an enzyme that metabolizes dopamine. Objectives. We investigated five single-nucleotide polymorphisms in addition to the functional Val158Met variant spanning the COMT gene for association with TD. Methods. We analyzed the six COMT single-nucleotide polymorphisms in a sample of schizophrenia/schizoaffective disorder patients (n=226; 196 Caucasians and 30 African Americans). Results. We found a significant association between the marker rs165599 in the 3′ untranslated region of COMT and TD (AA versus G-carrier: ORAA2.22, 95\% CI:1.234.03; P=0.007). The association appeared to be originating from males. We did not find a significant association of the other five tested polymorphisms with TD in our samples. We performed a sex-stratified meta-analysis across all of the published studies (n6 plus our own data) of COMT and TD, and found an association between ValVal genotype and TD in females (ORValVal1.63, 95\% CI: 1.092.45; P=0.019) but not in males. Conclusions. Overall, our results suggest that the COMT gene may have a minor but consistent role in TD, although sex-stratified studies with additional markers in larger clinical samples should be performed.",

keywords = "COMT, Meta-analysis, Pharmacogenetics, Schizophrenia, Tardive dyskinesia",

author = "Zai, \{Clement C.\} and Tiwari, \{Arun K.\} and M{\"u}ller, \{Daniel J.\} and \{De Luca\}, Vincenzo and Takahiro Shinkai and Sajid Shaikh and Xingqun Ni and David Sibony and Voineskos, \{Aristotle N.\} and Meltzer, \{Herbert Y.\} and Lieberman, \{Jeffrey A.\} and Potkin, \{Steven G.\} and Gary Remington and Kennedy, \{James L.\}",

note = "Funding Information: AKT, DJM, VdL, TS, SS; XN, DS, ANV, GR report no competing interests. CCZ and JLK: patent application for “ marker for tardive dyskinesia” . HYM has received grants and/or has been a consultant to: Abbott Labs, ACADIA, Eli Lilly, Janssen, Pfizer, Wyeth, Schering Plough, SureGene, Novartis, Azur, Biovail, Lundbeck, Roche, Otsuka, Dainippon Sumitomo, Cephalon, Minster, Bristol Myers Squibb, Astra Zeneca, Glaxo-Smith-Kline, Memory, 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; and he holds a patent from Repligen. JLK has been a consultant to GSK, Sanofi-Aventis, Dainippon-Sumitomo. Funding Information: We thank the authors of the papers included in the meta-analysis for providing genotype information for their samples. We also thank the Canadian Institute for Health Research – postdoctoral fellowship to AKT; 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, as well as the Bebensee Foundation to CCZ. We further thank the participants in the study.",

year = "2010",

month = sep,

doi = "10.3109/15622975.2010.486043",

language = "English (US)",

volume = "11",

pages = "803--812",

journal = "World Journal of Biological Psychiatry",

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T1 - The catechol-O-methyl-transferase gene in tardive dyskinesia

AU - Zai, Clement C.

AU - Tiwari, Arun K.

AU - Müller, Daniel J.

AU - De Luca, Vincenzo

AU - Shinkai, Takahiro

AU - Shaikh, Sajid

AU - Ni, Xingqun

AU - Sibony, David

AU - Voineskos, Aristotle N.

AU - Meltzer, Herbert Y.

AU - Lieberman, Jeffrey A.

AU - Potkin, Steven G.

AU - Remington, Gary

AU - Kennedy, James L.

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PY - 2010/9

Y1 - 2010/9

N2 - Tardive dyskinesia (TD) is a severe and potentially irreversible motor side effect linked to long-term antipsychotic exposure. Changes in dopamine neurotransmission have been implicated in the etiology of TD, and catechol-O-methyl-transferase (COMT) is an enzyme that metabolizes dopamine. Objectives. We investigated five single-nucleotide polymorphisms in addition to the functional Val158Met variant spanning the COMT gene for association with TD. Methods. We analyzed the six COMT single-nucleotide polymorphisms in a sample of schizophrenia/schizoaffective disorder patients (n=226; 196 Caucasians and 30 African Americans). Results. We found a significant association between the marker rs165599 in the 3′ untranslated region of COMT and TD (AA versus G-carrier: ORAA2.22, 95% CI:1.234.03; P=0.007). The association appeared to be originating from males. We did not find a significant association of the other five tested polymorphisms with TD in our samples. We performed a sex-stratified meta-analysis across all of the published studies (n6 plus our own data) of COMT and TD, and found an association between ValVal genotype and TD in females (ORValVal1.63, 95% CI: 1.092.45; P=0.019) but not in males. Conclusions. Overall, our results suggest that the COMT gene may have a minor but consistent role in TD, although sex-stratified studies with additional markers in larger clinical samples should be performed.

AB - Tardive dyskinesia (TD) is a severe and potentially irreversible motor side effect linked to long-term antipsychotic exposure. Changes in dopamine neurotransmission have been implicated in the etiology of TD, and catechol-O-methyl-transferase (COMT) is an enzyme that metabolizes dopamine. Objectives. We investigated five single-nucleotide polymorphisms in addition to the functional Val158Met variant spanning the COMT gene for association with TD. Methods. We analyzed the six COMT single-nucleotide polymorphisms in a sample of schizophrenia/schizoaffective disorder patients (n=226; 196 Caucasians and 30 African Americans). Results. We found a significant association between the marker rs165599 in the 3′ untranslated region of COMT and TD (AA versus G-carrier: ORAA2.22, 95% CI:1.234.03; P=0.007). The association appeared to be originating from males. We did not find a significant association of the other five tested polymorphisms with TD in our samples. We performed a sex-stratified meta-analysis across all of the published studies (n6 plus our own data) of COMT and TD, and found an association between ValVal genotype and TD in females (ORValVal1.63, 95% CI: 1.092.45; P=0.019) but not in males. Conclusions. Overall, our results suggest that the COMT gene may have a minor but consistent role in TD, although sex-stratified studies with additional markers in larger clinical samples should be performed.

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The catechol-O-methyl-transferase gene in tardive dyskinesia

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ASJC Scopus subject areas

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