Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders
Abstract
Catechol-O-methyltransferase (COMT) inactivates catecholamines and catechol drugs such as L-DOPA. A common genetic polymorphism in humans is associated with a three-to-four-fold variation in COMT enzyme activity and is also associated with individual variation in COMT thermal instability. We now show that this is due to G-->A transition at codon 158 of the COMT gene that results in a valine to methionine substitution. The two alleles can be identified with a PCR-based restriction fragment length polymorphism analysis using the restriction enzyme Nla III. The identification of a gentic marker associated with significant alterations in enzyme activity will facilitate the analysis of a possible role for the COMT gene in neuropsychiatric conditions in which abnormalities in catecholamine neurotransmission are believed to occur, including mood disorders, schizophrenia, obsessive compulsive disorder, alcohol and substance abuse, and attention deficit hyperactivity disorder. In addition, this polymorphism may have pharmacogenetic significance in that it will help make it possible to identify patients who display altered metabolism of catechol drugs.
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In BD, dysregulation of dopamine metabolism may contribute to the signature mood instability.
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The Met allele of COMT Val158Met decreases COMT activity.
“the Met allele of the Val158 Met polymorphism (rs4680) is known to decrease COMT activity (43).”
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de Jong, M. M., Nolte, I. M., Meerman, G. J. T., van der Graaf, W. T. A., Oosterwijk, J. C., Kleibeuker, J. H., Schaapveld, M., & de Vries, E. G. E. (2002) · Journal of Medical Genetics · doi:10.1136/jmg.39.4.225 · Cited by 235 · see citing works
Dauvilliers, Y. A., Mayer, G., Lecendreux, M., et al. (2002) · Neurology · doi:10.1212/01.wnl.0000036605.89977.d0 · Cited by 228 · see citing works
Prepulse inhibition and genetic mouse models of schizophrenia
Powell, S. B., Zhou, X., & Geyer, M. A. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.04.021 · Cited by 218 · see citing works
AVPR1a and SLC6A4 Gene Polymorphisms Are Associated with Creative Dance Performance
Bachner‐Melman, R., Christian Dina, C., Zohar, A. H., Constantini, N., Lerer, E., Hoch, S., Sella, S., Nemanov, L., Gritsenko, I., Lichtenberg, P., et al. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0010042 · Cited by 222 · see citing works
“These included the dopamine D5 microsatellite marker (DRD5), linked in some studies to attention deficit [33,34], the insulin-like growth factor 2 (IGF2, three single nucleotide polymorphisms), linked to eating disorders and self-report measures of altruism [15,35], catechol-O-methyltransferase (COMT) [36], linked to…”
BackgroundEtnier (1997) · doi:10.1523/jneurosci.4975-05.2006 · Cited by 219 · see citing works
“The COMT gene contains a G to A missense variant (Lachman et al., 1996) that translates into a substitution of methionine for valine at codon 158 (Val (158)Met), such that the enzyme containing Met 158 has significantly less activity and presumably greater synaptic dopamine than the Val 158 enzyme (Lotta et al.”
BackgroundGenetics of alcohol and tobacco use in humans
Tyndale, R. F. (2003) · Annals of Medicine · doi:10.1080/07853890310010014 · Cited by 219 · see citing works
Strous, R. D., Bark, N. M., Parsia, S. S., Volavka, J., & Lachman, H. M. (1997) · Psychiatry Research · doi:10.1016/s0165-1781(96)03111-3 · Cited by 217 · see citing works
Self-citationCraddock, N., Owen, M. J., & O'Donovan, M. C. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001808 · Cited by 216 · see citing works
Brody, A. L., Mandelkern, M. A., Olmstead, R. E., Scheibal, D., Hahn, E. L., Shiraga, S., Zamora-Paja, E., Farahi, J. B., Saxena, S., London, E. D., et al. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.7.808 · Cited by 208 · see citing works
Gadad, B. S., Jha, M. K., Czysz, A., Furman, J. L., Mayes, T. L., Emslie, M. P., & Trivedi, M. H. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.07.001 · Cited by 205 · see citing works
“…polymorphisms in the multidrug-resistance gene (MDR1) are associated with both positive (Dong et al., 2009; Gex-Fabry et al., 2008; Kato et al., 2008; Nikisch et al., 2008; Uhr et al., 2008) and negative (Laika et al., 2006; Mihaljevic Peles et al., 2008; Peters et al., 2008) treatment outcomes.”
Genetic predictors for acute experimental cold and heat pain sensitivity in humans
Kim, H., Mittal, D. P., Iadarola, M. J., & Dionne, R. A. (2006) · Journal of Medical Genetics · doi:10.1136/jmg.2005.036079 · Cited by 206 · see citing works
Hall, K. T., Lembo, A. J., Kirsch, I., Ziogas, D. C., Douaiher, J., Jensen, K. B., Conboy, L. A., Kelley, J. M., Kokkotou, E. G., & Kaptchuk, T. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048135 · Cited by 204 · see citing works
“COMT val158met, is a G to A transition leading to amino-acid substitution at codon 158 in the transmembrane form of the enzyme [8].”
BackgroundArbelle, S., Benjamin, J., Golin, M., Kremer, I., Belmaker, R. H., & Ebstein, R. P. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.4.671 · Cited by 202 · see citing works
“Three additional polymorphisms of considerable interest in human behavioral genetics—the dopamine D4 receptor (DRD4) (17), catechol O-methyltransferase (COMT) (18), and the MAOA promoter region (MAOA) (19)—were also examined for association with shyness in our study sample.”
BackgroundInfluentialCatechol‐ O ‐methyltransferase and Its Inhibitors in Parkinson's Disease
Bonifácio, M. J., Palma, P. N., Almeida, L., & Soares-da-Silva, P. (2007) · CNS Drug Reviews · doi:10.1111/j.1527-3458.2007.00020.x · Cited by 201 · see citing works
“The Met108/158 variant is associated with low enzymatic activity and decreased thermal stability, while the Val108/158 is associated with high activity (Lachman et al. 1996; Lotta et al. 1995).”
BackgroundLachman, H. M., Nolan, K. A., Mohr, P., Saito, T., & Volavka, J. (1998) · American Journal of Psychiatry · doi:10.1176/ajp.155.6.835 · Cited by 198 · see citing works
“The COMT codon 158 polymorphism was determined by restriction fragment length polymorphism analysis through use of polymerase chain reaction amplified gene fragments and Nla III restriction digestion, as previously described in detail (9).”
MethodSelf-citationCOMT genotype predicts cortical-limbic D1 receptor availability measured with [11C]NNC112 and PET
Slifstein, M., Kolachana, B. S., Simpson, E. H., Tabares, P., Cheng, B., Duvall, M., Frankle, W. G., Weinberger, D. R., Laruelle, M. A., & Abi‐Dargham, A. (2008) · Molecular Psychiatry · doi:10.1038/mp.2008.19 · Cited by 195 · see citing works
Joober, R., Gauthier, J., Lal, S., Bloom, D., Lalonde, P., Rouleau, G. A., Benkelfat, C., & Labelle, A. (2002) · Archives of General Psychiatry · doi:10.1001/archpsyc.59.7.662 · Cited by 197 · see citing works
Benjamin, J., Osher, Y., Kotler, M., Gritsenko, I., Nemanov, L., Belmaker, R. H., & Ebstein, R. P. (2000) · Molecular Psychiatry · doi:10.1038/sj.mp.4000640 · Cited by 196 · see citing works
Oxidants and Antioxidants in Breast Cancer
Ambrosone, C. B. (2000) · Antioxidants and Redox Signaling · doi:10.1089/ars.2000.2.4-903 · Cited by 191 · see citing works
- Authors
- Lachman, H. M., Papolos, D. F., Saito, T., Yu, Y.-M., Szumlanski, C. L., & Weinshilboum, R. M.
- Affiliations
- Albert Einstein College of Medicine (US)
- Mayo Clinic (US)
- Venue
- Pharmacogenetics
- Published
- 1996-06
- Volume
- 6
- Issue
- 3
- Pages
- 243-250
- ISSN
- 0960-314X (ISSN-L)
- OpenAlex
- W2100040984
- Cited by
- 1,788
- References
- 0
- Citations by year
- 2026: 12 · 2025: 28 · 2024: 28 · 2023: 26 · 2022: 39 · 2021: 53 · 2020: 86 · 2019: 45 · 2018: 44 · 2017: 75 · 2016: 77 · 2015: 92 · 2014: 99 · 2013: 98 · 2012: 105
- FWCI
- 14.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacogenetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01-GM-28157, R01 GM 35720, R01GM028157, R01GM035720)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- catechol-O-methyltransferase, COMT gene, COMT Val158Met polymorphism, genetic polymorphism, enzyme activity variation, thermal instability, catecholamine metabolism, L-dopa metabolism, neuropsychiatric disorders, mood disorders, schizophrenia, obsessive-compulsive disorder, alcohol and substance abuse, attention deficit hyperactivity disorder, genetic markers
- MeSH terms
- Catechol O-Methyltransferase, Genotype, Heterozygote, Homozygote, Humans, Molecular Sequence Data, Pharmacogenetics, Phenotype, Polymorphism, Genetic, Schizophrenia, Mood Disorders
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