The SNP Peek series brings you concise, up-to-date information on genetic variations known as Single Nucleotide Polymorphisms (SNPs), which affect a significant percentage of patients. The SNPs featured in this series are clinically relevant, nutritionally actionable and validated by published research. Featuring one SNP at a time, the series will educate readers about prevalence, important research findings, targeted nutritional supplements and monitoring.‡
COMT (Catechol O-Methyltransferase) Val158Met (rs4680)
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COMT is an enzyme that degrades dopamine, a critical neurotransmitter that regulates cognition and behavior.1-4 COMT also detoxifies estradiol.5 The Val158Met SNP is among the most extensively researched genetic variations in psychiatry.1-4, 6-14 The Val allele increases COMT enzyme activity, while the Met allele limits COMT activity to 25% of its normal function, allowing dopamine and estrogen to reach higher levels.1-5
Figure 1. Dopamine, a stimulant neurotransmitter derived from L-tyrosine, supports mental sharpness, working memory and other aspects of cognitive performance. COMT degrades dopamine, limiting its availability and actions. COMT activity is largely determined by the Val158Met SNP.
Who is Affected?
The majority of the world’s population is homozygous for the wild-type allele (known as GG, -/- or Val/Val). An estimated 20-30% of Caucasians of European ancestry are homozygous for the Met allele (Met/Met, also known as AA or +/+). This genotype appears to be less common in Asian and African populations.6
- Stress tolerance. The Val/Val (GG or -/-) genotype is associated with better cognitive and psychological tolerance of stressful situations. Conversely, the Met allele has been associated with nervousness, worry and fear.4
- Cognitive performance. The Met/Met (AA or +/+) genotype is associated with better performance in memory and attention tasks than other genotypes. This advantage of the Met allele is likely a result of heightened dopaminergic neurotransmission in the prefrontal cortex. However, the effect may be diminished under stressful conditions.4
- Response to stimulants. Stimulant drugs reduce cognitive function in Met carriers. Conversely, they tend to improve cognition in Val carriers.7
- Estrogen metabolism. The Met allele may increase levels of estradiol due to decreased methylation of this hormone.5
- In two clinical studies, subjects with at least one Met allele exhibited better executive function and performance on memory tasks than subjects with Val/Val genotypes.8-9
- The Met allele may reduce caffeine tolerance. In a cohort of 773 men, heavy coffee consumption was associated with cardiovascular events in Met allele carriers.10
- The COMT Val allele may exacerbate elevated homocysteine levels in MTHFR T/T (+/+) genotypes, according to a study of 780 elderly adults.11 In patients with elevated homocysteine, it is prudent to ensure adequate folate, B6 and B12 intake.‡
Diet and Lifestyle Recommendations‡
- For Val/Val (-/-) and Val/Met (-/+) genotypes. Consume adequate protein, which provides amino acid precursors of dopamine and norepinephrine. Exercise also supports daily cognitive function, alertness, energy and mood.
- For Met/Met (+/+) genotypes. Consider relaxation techniques, psychotherapy and/or meditation to manage stress. To support restful sleep, practice sleep hygiene techniques and consider magnesium supplementation. Use caution with caffeine and other stimulants, which magnify the effects of emotional stress. Include cruciferous vegetables as part of a whole-food based diet to support estrogen metabolism.‡
Pure Encapsulations® Products:
For Met/Met (+/+) genotypes
- SAMe is the methyl donor for COMT. SAMe also supports cognitive function and mood through other mechanisms.‡
- Magnesium (glycinate) supports healthy stress responses by virtue of its role in COMT-independent neurotransmitter systems.‡
- Lithium (orotate) or Lithium liquid may be beneficial in supporting mood and neurocognitive health.‡
- Adenosyl/Hydroxy B12 or Adenosyl/Hydroxy B12 liquid may be preferable to methylcobalamin because it tends to be less stimulating, according to unpublished case reports.
- DIM Detox supports estrogen detoxification.‡
For Val/Val (-/-) and Val/Met (-/+) genotypes
- DopaPlus provides dopamine precursors (L-tyrosine and L-DOPA) and cofactors (zinc, vitamin B6 and folate) to promote the production of dopamine to support daily cognitive function and performance on mental tasks.‡
- Rhodiola Rosea maintains healthy adrenal catecholamine activity and may support energy levels.‡
Because neurotransmission and hormone metabolism depend on many interacting genetic and environmental factors, not all individuals with COMT variants will show clinical manifestations or require specific support.
Product selection should consider other factors, such as nutrient status (refer to suggested monitoring below), appraisal of mental and cognitive function, and other relevant information obtained in the patient evaluation.‡
Assessment and Monitoring:
- Magnesium has no direct relationship to COMT, but is critical for healthy stress responses, cognitive performance and emotional wellness, irrespective of genotype. RBC magnesium reflects intracellular stores of this essential mineral.‡
- Estrogen methylation ratio (2-OHE1:2-OMeE1) indicates how effectively a patient methylates estrogen.
To Learn More:
The following databases provide abstracts of published studies, scholarly reviews and other types of articles with reliable, up-to-date information. To retrieve all relevant published studies on COMT Val158Met, enter the accession number (rs4680) in the search field. Full text articles are available in open-access journals only.
Google Scholar: scholar.google.com
PureGenomics® is a platform combining educational tools, protocols, core products, and E-script—our electronic prescription service—with PureGenomics.com, our dynamic, practitioner-exclusive website application. PureGenomics.com is designed to help identify common genetic variations known as Single Nucleotide Polymorphisms (SNPs) that are clinically relevant and nutritionally actionable.‡
This unique platform makes it easy to TEST, TRANSLATE and TARGET SNPs with the right nutritional support, empowering practitioners with precision and confidence in the pursuit of optimal health for every patient.‡
Learn how to successfully implement PureGenomics® in your practice today!
Learn more in the PureGenomics® Methylation Protocol
1. Craddock N, Owen MJ, O’Donovan MC. Mol Psychiatry 2006;11(5):446-58.
2. Lachman HM. Neuropsychopharmacology 2008;33(13):3027-9.
3. Lachman HM, Papolos DF, Saito T, et al. Pharmacogenetics 1996;6:243- 50.
4. Stein DJ, Newman TK, Savitz J, Ramesar R. CNS Spectr 2006 Oct;11(10):745-8.
5. Zhu BT, Conney AH. Carcinogenesis 1998;19:1-27
6. HapMap Consortium data. ftp://ftp.ncbi.nlm.nih.gov/hapmap.
7. Hamidovic A, Dlugos A, Palmer AA, de Wit H. Psychiatr Genet 2010;20(3):85-92.
8. Goldberg TE, Egan MF, Gscheidle T, et al. Arch Gen Psychiatry 2003;60:889-96.
9. de Frias CM, Annerbrink K, Westberg L, et al. Behav Genet 2004;34:533-9.
10. Happonen P, Voutilainen S, Tuomainen TP, Salonen JT. PLoS One 2006;27(1):e117.
11. Tunbridge EM, Harrison PJ, Warden DR, et al. Am J Med Genet B Neuropsychiatr Genet 2008;147B(6): 996-9.
12. Zhang X, Li J, Qin W, et al. Sci Rep 2015;5:10105.
13. Meyer-Lindenberg A, Weinberger DR. Nat Rev Neurosci 2006;7(10):818- 27.
14. Roffman JL, Weiss AP, Deckersbach T, et al. Am J Med Genet B Neuropsychiatr. Genet 2008;147B: 990-5.