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COMT: Function & Health Implications of a Dopamine Gene

Written by Puya Yazdi, MD | Last updated:
Nattha Wannissorn
Medically reviewed by
Nattha Wannissorn, PhD | Written by Puya Yazdi, MD | Last updated:

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One mutation in the COMT gene may change the way we experience stress and pain. Are you a worrier or a warrior? Read on to find out.

What is COMT?

Catechol-O-Methyltransferase (COMT) is one of several enzymes that degrade dopamine, epinephrine, and norepinephrine. COMT breaks down dopamine mostly in the part of the brain responsible for higher cognitive and executive function (prefrontal cortex) [1].

Role in Methylation

Catechol-O-Methyltransferase is an enzyme that transfers methyl groups (hence the name methyltransferase).

COMT introduces a methyl group to the catecholamine (dopamine, epinephrine, and norepinephrine), which is donated by S-adenosylmethionine (SAM). SAM is required for COMT to work properly [2].

Having too little SAM (s-adenosylmethionine) and too much SAH (s-adenosylhomocysteine) from undermethylation results in COMT inhibition as well [3].

A study of adolescent substance use (cigarette smoking, alcohol, and cannabis) found a complex association between COMT methylation and substance abuse [4].

COMT V158M (rs4680) & Its Health Effects

One of the most researched variants in the human genome is a point mutation in the COMT gene called V158M (or rs4680). It has been associated with differences in intelligence, personality, and disease risk.

Enzyme Activity

The A allele results in 3 to 4-fold decrease in COMT enzyme activity [5, 6].

This gene variant has been associated with differences in cognitive flexibility, impulse control, abstract thought, and being able to follow rules or task structure [1].

Dopamine Levels

If you have AA then you will have the highest dopamine, while GG results in the lowest dopamine. AG is somewhere in the middle; the difference between AA and GG is studied more often than the difference between either homozygous genotype and AG. Meanwhile, very high and very low dopamine have each been associated with decreased cognitive performance [7, 8].

Under stress, dopamine increases. High dopamine producers (AA genotype) have been found to perform worse under stress, possibly because their dopamine levels are too high for optimal cognitive function. By the same logic, low dopamine producers (GG genotype) may potentially perform better under stress [7].

Gender Differences

COMT is decreased by estrogen [9], such that overall COMT activity in prefrontal cortex and other tissues is about 30% lower in women and girls than men and boys [10]. This diminished COMT activity translates to about 30% higher baseline dopamine levels in women than men [11].

Therefore, some researchers have suggested that SNPs that result in lower COMT (such as the A allele for rs4680) may be beneficial for men. Indeed, men with lower COMT have demonstrated improved performance on tasks dependent on the prefrontal cortex, whereas women have not [11].

Cognitive Function

Here’s a summary of cognitive scores on tests taken by AA/AG/GG.

  • Met/Met = AA; High dopamine in prefrontal cortex.
  • Val/Met = AG; Higher dopamine in prefrontal cortex (not as high as AA).
  • Val/Val = GG; Lower dopamine in prefrontal cortex.
  • PIQ = Performance IQ
  • VIQ = Verbal IQ

In one study, people with the AG genotype tended to have the best IQ scores (both verbal and performance IQ) and best cognitive scores overall. However, this study did not find statistically significant differences in most metrics [12].

In the same study, people with AA and AG genotypes had superior performance relative to GG on reading-related skills and marginally better performance for the decoding skill. However, there was no significant difference in more general language skills (Oral Language, Comprehension) or IQ [12].

The brains of people in the AA group experienced the greatest activation in areas responsible for reading comprehension (frontal lobe). People with the AA genotype were also found to be the best readers, overall [12].

Screenshot 2014-12-25 09.31.41[13]

Performance IQ (PIQ)+Verbal IQ (VIQ)= Total IQ

Screenshot 2014-12-25 09.41.34

Personality Traits

Lower dopamine producers (people with the GG genotype) have been found to be more extraverted and less neurotic [14].

  • Met/Met=AA; High dopamine in prefrontal cortex.
  • Val/Val= GG; Lower dopamine in prefrontal cortex.

Screenshot 2014-12-25 10.31.05

Ethnic Differences

G allele frequencies: East Asians have 71% G’s, Africans 69% G’s Americans 61% G’s, Europeans 48% G’s [15].


The following SNPs can also affect the activity of your COMT gene:

  • Rs4633 – boys with TT had worse cognitive performance when acutely exposed to mercury [16].
  • Rs6269 – boys with AA had worse cognitive performance when acutely exposed to mercury [16].
  • Rs165599 – The G allele is associated with Bipolar 1 and GG is associated with poorer performance on verbal memory and learning test in healthy people compared to AA/AG (lower dopamine in the prefrontal cortex). It’s assumed that the worse verbal memory performance contributes to Bipolar [17].
  • Rs737865 – Haplotype associated with panic and anxiety disorder: rs737865 (T), rs4680 (G) and rs165599 (G) [18].

About the Author

Puya Yazdi

Puya Yazdi

Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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