Catechol‐O‐methyltransferase gene methylation and substance use in adolescents: the TRAILS study
Open accessAbstract
Substance use often starts in adolescence and poses a major problem for society and individual health. The dopamine system plays a role in substance use, and catechol-O-methyltransferase (COMT) is an important enzyme that degrades dopamine. The Val(108/158) Met polymorphism modulates COMT activity and thus dopamine levels, and has been linked to substance use. COMT gene methylation, on the other hand, may affect expression and thus indirectly COMT activity. We investigated whether methylation of the COMT gene was associated with adolescents' substance use. Furthermore, we explored whether the COMT Val(108/158) Met polymorphism interacts with COMT gene methylation in association with substance use. In 463 adolescents (mean age=16, 50.8% girls), substance use (cigarette smoking, alcohol and cannabis use) was assessed with self-report questionnaires. From blood samples, COMT Val(108/158) Met genotype and methylation rates of membrane bound (MB) and soluble (S) COMT promoters were assessed. MB-COMT promoter methylation was associated with non-daily smoking [odds ratio (OR)=1.82, P=0.03], but not with daily smoking (OR=1.20, P=0.34), MB-COMT promoter methylation was not associated with alcohol use. Adolescents with the Met/Met genotype and high rates of MB-COMT promoter methylation were less likely to be high-frequent cannabis users than adolescents with the Val/Val or Val/Met genotype. S-COMT promoter methylation was not associated with substance use. These results indicate that there is an association between substance use and COMT gene methylation. Although this association is complex, combining genetic and epigenetic variation of the COMT gene may be helpful in further elucidating the influence of the dopamine system on substance use in adolescence.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Cannabis use interacts with the COMT Val158Met genotype/epigenotype to influence psychosis risk.
“cannabis use interacts with the COMT Val158Met genotype/epigenotype to influence psychosis risk”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [81]
Cites
A simple salting out procedure for extracting DNA from human nucleated cells
Miller, S. A., Dykes, D. D., & Polesky, H. F. (1988) · Nucleic Acids Research · doi:10.1093/nar/16.3.1215 · Cited by 20,341 · see citing works
The neural basis of drug craving: An incentive-sensitization theory of addiction
Robinson, T. (1993) · Brain Research Reviews · doi:10.1016/0165-0173(93)90013-p · Cited by 7,346 · see citing works
DNA methylation age of human tissues and cell types
Horvath, S. (2013) · Genome Biology · doi:10.1186/gb-2013-14-10-r115 · Cited by 7,075 · see citing works
Lachman, H. M., Papolos, D. F., Saito, T., Yu, Y.-M., Szumlanski, C. L., & Weinshilboum, R. M. (1996) · Pharmacogenetics · doi:10.1097/00008571-199606000-00007 · Cited by 1,788 · cited 1× · see citing works
“The functional Val108/158Met single nucleotide polymorphism (SNP) in the COMT gene, rs4680, has been associated with altered COMT activity (Lachman et al. 1996).”
BackgroundBecker, J. B., & Hu, M. (2008) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2007.07.003 · Cited by 1,003 · see citing works
Catecholamine theories of reward: A critical review
Wise, R. A. (1978) · Brain Research · doi:10.1016/0006-8993(78)90253-6 · Cited by 769 · see citing works
Macleod, J., Oakes, R., Copello, A., Crome, I., Egger, M., Hickman, M., Oppenkowski, T., Stokes-Lampard, H., & Smith, G. D. (2004) · The Lancet · doi:10.1016/s0140-6736(04)16200-4 · Cited by 639 · see citing works
Volkow, N. D., Wang, G., Fowler, J. S., Tomasi, D., Telang, F., & Baler, R. (2010) · BioEssays · doi:10.1002/bies.201000042 · Cited by 532 · see citing works
Postcocaine anhedonia. An animal model of cocaine withdrawal.
Markou, A., & Koob, G. F. (1991) · PubMed · Cited by 505 · see citing works
Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder
Abdolmaleky, H. M., Cheng, K.-H., Faraone, S. V., Wilcox, M., Glatt, S. J., Gao, F., Smith, C. L., Shafa, R., Aeali, B., Carnevale, J., et al. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl253 · Cited by 462 · see citing works
Continuous Aging of the Human DNA Methylome Throughout the Human Lifespan
Johansson, Å., Enroth, S., & Gyllensten, U. B. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067378 · Cited by 381 · see citing works
TENHUNEN, J., SALMINEN, M., LUNDSTRÖM, K., KIVILUOTO, T., SAVOLAINEN, R., & ULMANEN, I. (1994) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1994.tb19083.x · Cited by 331 · see citing works
Cohort Profile: The Dutch 'TRacking Adolescents' Individual Lives' Survey'; TRAILS
Huisman, M. A., Oldehinkel, A. J., de Winter, A., Minderaa, R. B., de Bildt, A. A., Huizink, A. C., Verhulst, F. C., & Ormel, J. (2008) · International Journal of Epidemiology · doi:10.1093/ije/dym273 · Cited by 302 · see citing works
Self-citationChromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1→q11.2
Grossman, M. H., Emanuel, B. S., & Budarf, M. L. (1992) · Genomics · doi:10.1016/0888-7543(92)90316-k · Cited by 296 · see citing works
Phasic dopamine release in appetitive behaviors and drug addiction
Wanat, M., Willuhn, I., Clark, J., & Phillips, P. (2009) · Current Drug Abuse Reviewse · doi:10.2174/1874473710902020195 · Cited by 177 · see citing works
van der Knaap, L. J., Riese, H., Hudziak, J. J., Verbiest, M. M. P. J., Verhulst, F. C., Oldehinkel, A. J., & van Oort, F. V. A. (2014) · Translational Psychiatry · doi:10.1038/tp.2014.22 · Cited by 165 · see citing works
Self-citationMAOA methylation is associated with nicotine and alcohol dependence in women
Philibert, R. A., Gunter, T. D., Beach, S. R. H., Brody, G. H., & Madan, A. (2008) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30778 · Cited by 162 · see citing works
Beuten, J., Payne, T. J., Ma, J. Z., & Li, M. D. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300997 · Cited by 136 · see citing works
Ormel, J., Oldehinkel, A. J., Sijtsema, J. J., van Oort, F. V. A., Raven, D., Veenstra, R., Vollebergh, W., & Verhulst, F. C. (2012) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2012.08.004 · Cited by 130 · see citing works
Self-citationEpigenetics of drug abuse: predisposition or response
Nielsen, D. A., Utrankar, A., Reyes, J. A., Simons, D. D., & Kosten, T. R. (2012) · Pharmacogenomics · doi:10.2217/pgs.12.94 · Cited by 125 · see citing works
Hillemacher, T., Frieling, H., Hartl, T., Wilhelm, J., Kornhuber, J., & Bleich, S. (2008) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2008.04.006 · Cited by 125 · see citing works
Moderators of the association between peer and target adolescent substance use
Marschall-Lévesque, S., Ryan, N. C., Vitaro, F., & Séguin, J. R. (2013) · Addictive Behaviors · doi:10.1016/j.addbeh.2013.09.025 · Cited by 113 · see citing works
Association analysis of the DRD4 and COMT genes in methamphetamine abuse
Li, T., Chen, C. Y., Hu, X., Ball, D., Lin, S., Chen, W., Sham, P. C., Loh, E., Murray, R. M., & Collier, D. A. (2004) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30024 · Cited by 105 · see citing works
Relationship between dopamine system genes and extraversion and novelty seeking
Голимбет, В. Е., Алфимова, М. В., Gritsenko, I. K., & Ebstein, R. P. (2007) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-007-0058-8 · Cited by 105 · see citing works
Murphy, B. C., O'Reilly, R. L., & Singh, S. M. (2005) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30134 · Cited by 102 · see citing works
Personality and Substance Use Among Adolescents: a longitudinal study
Teichman, M., Barnea, Z., & RAVAV, G. (1989) · British Journal of Addiction · doi:10.1111/j.1360-0443.1989.tb00567.x · Cited by 77 · see citing works
Lang, U. E., Bajbouj, M., Sander, T., & Gallinat, J. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301335 · Cited by 73 · see citing works
Are genetic variants of COMT associated with addiction?
Tammimäki, A., & Männistö, P. T. (2010) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e328340bdf2 · Cited by 67 · see citing works
Sasaki, M., Kaneuchi, M., Sakuragi, N., & Dahiya, R. (2003) · PubMed · Cited by 64 · see citing works
Developmental Trajectories of Marijuana Use From Adolescence to Adulthood
Brook, J. S., Zhang, C., & Brook, D. W. (2011) · Archives of Pediatrics and Adolescent Medicine · doi:10.1001/archpediatrics.2010.248 · Cited by 63 · see citing works
Nijmeijer, J. S., Hartman, C. A., Rommelse, N. N. J., Altink, M. E., Buschgens, C. J. M., Fliers, E. A., Franke, B., Minderaa, R. B., Ormel, J., Sergeant, J. A., et al. (2010) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2010.02277.x · Cited by 57 · see citing works
Self-citationStrobel, A., Lesch, K., Jatzke, S., Paetzold, F., & Brocke, B. (2003) · Molecular Psychiatry · doi:10.1038/sj.mp.4001253 · Cited by 54 · see citing works
Creemers, H. E., Harakeh, Z., Dick, D. M., Meyers, J. L., Vollebergh, W., Ormel, J., Verhulst, F. C., & Huizink, A. C. (2010) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2010.10.008 · Cited by 42 · see citing works
Self-citationSasaki, M., Karube, A., Karube, Y., Sakuragi, N., Fujimoto, S., & Dahiya, R. (2004) · International Journal of Gynecological Cancer · doi:10.1136/ijgc-00009577-200409001-00078 · Cited by 39 · see citing works
Demetrovics, Z., Varga, G., Székely, A., Vereczkei, A., Csorba, J., Balázs, H., Hoffman, K., Sasvári‐Székely, M., & Barta, C. (2010) · Comprehensive Psychiatry · doi:10.1016/j.comppsych.2009.11.008 · Cited by 38 · see citing works
Hosák, L., Libiger, J., Čı́žek, J., Beránek, M., & Čermáková, E. (2006) · PubMed · Cited by 32 · see citing works
Xu, Q. (2010) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2010.00016 · Cited by 32 · see citing works
The association between neurocognitive functioning and smoking in adolescence: The TRAILS study.
Harakeh, Z., de Sonneville, L. M. J., van den Eijnden, R. J. J. M., Huizink, A. C., Reijneveld, S. A., Ormel, J., Verhulst, F. C., Monshouwer, K., & Vollebergh, W. (2012) · Neuropsychology · doi:10.1037/a0029217 · Cited by 30 · see citing works
Self-citationRedden, D. T., Shields, P. G., Epstein, L. H., Wileyto, E. P., Zakharkin, S. O., Allison, D. B., & Lerman, C. E. (2005) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-04-0649 · Cited by 26 · see citing works
Hosák, L., Libiger, J., Cizek, J., Beránek, M., & Čermáková, E. (2007) · European Psychiatry · doi:10.1016/j.eurpsy.2007.01.625 · Cited by 19 · see citing works
Zhao, A., Cheng, Y., Li, X., Li, Q., Wang, L., Xu, J., Xiang, Y., Xing, Q., He, L., & Zhao, X. (2010) · Molecular Human Reproduction · doi:10.1093/molehr/gaq092 · Cited by 16 · see citing works
Plasticity genes do not modify associations between physical activity and depressive symptoms.
Stavrakakis, N., Oldehinkel, A. J., Nederhof, E., Voshaar, R. C. O., Verhulst, F. C., Ormel, J., & de Jonge, P. (2012) · Health Psychology · doi:10.1037/a0030111 · Cited by 15 · see citing works
Self-citationYoung (2000) · doi:10.1002/1096-8628(20001009)96:5
Flagged first, then by citations
Cited by
Sorted by citations
Barker, E. D., Walton, E., & Cecil, C. A. M. (2018) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12782 · Cited by 134 · see citing works
Can epigenetics shine a light on the biological pathways underlying major mental disorders?
Alameda, L., Trotta, G., Quigley, H., Rodriguez, V., Gadelrab, R., Dwir, D., Dempster, E., Wong, C. C. Y., & Forti, M. D. (2022) · Psychological Medicine · doi:10.1017/s0033291721005559 · Cited by 60 · see citing works
“…in DNAm associated with heavy CU in genes involved in dopamine transmission, such as DRD2 (Gerra et al., 2018), DAT1 (Grzywacz et al., 2020) and COMT (Van der Knaap et al., 2014) and in the CB1 and CB2 receptors genes part of the endocannabinoid system (Rotter et al., 2012; Tao et al., 2020).”
BackgroundInfluentialGene variants and educational attainment in cannabis use: mediating role of DNA methylation
Gerra, M. C., Jayanthi, S., Manfredini, M., Walther, D., Schroeder, J., Phillips, K. A., Cadet, J. L., & Donnini, C. (2018) · Translational Psychiatry · doi:10.1038/s41398-017-0087-1 · Cited by 42 · see citing works
Montel Hayes, R., Mason, C. E., & Miller, J. J. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1671122 · Cited by 5 · see citing works
“In the context of environmental interactions, cigarette smoking is associated with hypermethylation of the MB-COMT promoter, while cannabis use interacts with the COMT Val158Met genotype/epigenotype to in fl uence psychosis risk (80, 81).”
- Authors
- van der Knaap, L. J., Schaefer, J. M., Franken, I. H. A., Verhulst, F. C., van Oort, F. V. A., & Riese, H.
- Affiliations
- Department of Child and Adolescent Psychiatry & Psychology Erasmus Medical Center The Netherlands
- Erasmus MC (NL)
- University Medical Center Groningen (NL)
- Venue
- Genes, Brain and Behavior
- Publisher
- Wiley
- Published
- 2014-06-24
- Volume
- 13
- Issue
- 7
- Pages
- 618-625
- ISSN
- 1601-183X (ISSN-L)
- 1601-1848
- OpenAlex
- W2016644624
- Cited by
- 38
- References
- 44
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 4 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 2 · 2015: 7 · 2014: 1
- FWCI
- 2.28
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Genes Brain & Behavior (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Medical Research Council Program (GB-MW 940-38-011)
- ZonMW Brainpower (100-001-004)
- ZonMw Risk Behavior and Dependence (60-60600-97-118)
- ZonMw Culture and Health (261-98-710)
- Social Sciences Council Medium-sized Investment (GB-MaGW 480-01-006 and GB-MaGW 480-07-001)
- Social Sciences Council Project (GB-MaGW 452-04-314 and GB-MaGW 452-06-004)
- NWO Large-sized Investment (175.010.2003.005)
- NWO Longitudinal Survey and Panel Funding (481-08-013)
- Dutch Ministry of Justice
- European Science Foundation
- Biobanking and Biomolecular Resources Research Infrastructure BBMRI-NL
- Accare Center for Child and Adolescent Psychiatry
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- catechol-O-methyltransferase, adolescent substance use, cigarette smoking, alcohol consumption, cannabis use, dopaminergic system, epigenetics, promoter methylation, gene-environment interaction, TRAILS study
- MeSH terms
- Adolescent, Alcohol Drinking, Catechol O-Methyltransferase, Female, Humans, Male, Marijuana Smoking, Promoter Regions, Genetic, Smoking, Case-Control Studies, DNA Methylation, Polymorphism, Single Nucleotide
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
