COMT gene function:
The COMT gene codes for the enzyme catechol-O-methyltransferase which breaks down (metabolizes) the neurotransmitters dopamine, epinephrine, and norepinephrine. This enzyme adds a methyl group from SAMe to the dopamine, epinephrine, or norepinephrine molecules, thus changing them into a different substance.
COMT is also involved in the metabolism of some drugs used for asthma, Parkinson’s, and high blood pressure.
Researchers link COMT genetic variants to quite a variety of different diseases from mood disorders to heart disease. This variety is due to the COMT variants metabolizing neurotransmitters at different rates.
Some of the psychiatric disorder with increased risk associated with COMT variants include:
- bipolar disorder
Outside of the brain, COMT is also involved in the methylation of catechol estrogens.[ref][ref] This leads to differences in the amount of the COMT available in the prefrontal cortex between males and females after puberty. Estrogens can inhibit COMT, leading to an increase in dopamine in female brains. [ref] This also leads to
The COMT rs4680 AA variant is found in almost 20% of the population while the GG variant is found in 35-40% of the population. There are various health websites and Facebook groups dedicated to the negative effects of being ++ or — for this variant. I want to suggest that instead of focusing on any perceived negative effects, you should look at the various interactions between your genotype and diet/supplements/environment and use the information to optimize for your genes.
COMT Genetic Variants
COMT rs4680, Val158Met
One of the most studied variants of the COMT gene is rs4680, often referred to as Val158Met. In looking at research studies, the G is “Val” and the A allele is usually noted as “Met”.
- The G allele (Val) has higher COMT enzymatic activity, causing a more rapid breakdown of the neurotransmitters and thus lower levels of dopamine. In most populations, the G allele is the most common.[ref]
- The A allele (Met) has lower COMT enzyme activity and thus higher levels of dopamine. This variant of the COMT enzyme is said to have lower activity because it breaks down faster at normal body temperature.[ref]
Check your 23andMe results for rs4680 (v.4 and v.5):
- G/G: higher COMT activity, lower dopamine & norepinephrine, higher pain tolerance (Val)
- A/G: intermediate COMT activity
- A/A: 40% lower COMT activity, higher dopamine & norepinephrine, lower pain tolerance (Met)
Here are the findings from a few recent studies on this COMT variant:
- A 2015 study of cognitively normal adults found that those with GG genotype had lower Neuroticism scores and higher Agreeableness and Conscientiousness scores than those with AG or AA.[ref]
- A 2015 study of self-administered morphine in 973 patients following surgery found that the minor (A) allele was associated with more morphine use. This result backs up the many other studies showing that those with rs4680 AA often have a lower pain tolerance than those with rs4680 GG.[ref]
- A study of adolescent cannabis users found that those with the GG genotype (Val) were more likely to develop schizophrenia than those with the AA genotype. (The risk is still small.)[ref]
- A 2015 study of approximately 800 young adults looked at the combined effects of gender and COMT polymorphisms on schizophrenia and psychosis proneness traits. Males carrying the G allele scored higher on the negative symptoms and traits of schizophrenia and psychosis. [ref]
- A small 2014 study looked at the differences in fat oxidation and energy expenditure with green tea based on COMT genotype. Those with the rs4680 GG genotype had significantly increased energy expenditure and fat oxidation with green tea, while those with the AA genotype had no increase. [ref]
- Lots of other studies are listed on SNPedia including several that look at the response to antidepressants. There are hundreds of studies in PubMed on this COMT polymorphism.
This common variant is also involved in the activity level of COMT. T is the less common version with lower COMT enzyme activity; C is the more common version with higher activity. It is linked with the rs4680 polymorphism, and thus most people will have the same activity levels on both.
Check your 23andMe results for rs4633:
- C/C: higher COMT activity, lower dopamine, norepinephrine
- C/T: medium COMT activity
- T/T: lower COMT activity, higher dopamine, norepinephrine
Recent studies on this variant have found:
- Rs4633 TT is associated with less back pain with lower back disc degeneration [ref] [ref]
- A study of mercury exposure in children found that boys with the TT genotype had impaired test performance in response to increasing acute mercury exposure. This was in contrast to girls with the variant who showed fewer effects from acute mercury exposure. [ref]
- A study of atherosclerosis in an elderly Japanese population found that the CC genotype was associated with atherosclerosis, especially in women. [ref]
- A study found that those with TT had a higher risk of endometrial cancer. [ref]
Other COMT Polymorphisms:
A couple of COMT variants add to the effect of the main variants listed above.
Check your 23andMe results for rs6267 (v.4 and v.5):
Check your 23andMe results for rs165599 (v.4 and v.5):
Clinicians often suggest that those with the rs4680 AA genotype (lower COMT levels) avoid going overboard with foods and supplements that are considered methyl donors. Methyl donors include methylcobalamin (methyl-B12), curcumin, TMG, SAMe, theanine, and choline. [ref] The logic behind this suggestion is that overwhelming the pathway with too many methyl groups can lead to a sudden rise and then subsequent fall in dopamine levels — aka mood swings, anger, or anxiety.
Supplements that have a catechol structure are metabolized, or broken down, by COMT; this includes quercetin, EGCG, and luteolin [ref][ref]. If you have lower COMT enzyme activity, you may want to be careful of stacking too many supplements metabolized by COMT together at the same time.
A study in mice found that COMT deficiency led to glucose intolerance on a high-fat diet. Keeping in mind that this is just a mouse study, if you have blood sugar regulation issues and have COMT rs4680 AA, you may want to look at the amount of fat in your diet.
Magnesium is a cofactor for the COMT enzyme. A study found positive effects for liver COMT levels along with better heart health from supplementing with magnesium. A good quality magnesium supplement may be worth trying if you aren’t getting enough magnesium from food sources.
More to read:
- COMT and Heart Disease
- Will Vitamin E increase your risk of heart disease?
- Methylate Your Way To Mental Health -a podcast by Chris Masterjohn
- Methylation, a Chemical Reaction Critical to Life
- Understand COMT and Change Your Life! – Article from the American Board of Integrative Holistic Medicine.