Having trouble with supplements containing methyl groups? Wondering why your neurotransmitters are out of balance? It could be due to your COMT genetic variants. COMT is an important enzyme tasked with breaking down neurotransmitters, such as dopamine.
This article explains the COMT enzyme and how to check your genetic data for COMT fast and slow polymorphisms on 23 and Me, AncestryDNA, or similar data.
What does the COMT gene do?
The COMT gene encodes the catechol-O-methyltransferase enzyme, which breaks down (metabolizes) the neurotransmitters dopamine, epinephrine, and norepinephrine. It controls the amount of neurotransmitters available. It is also involved in the metabolism of estrogen metabolites, as well as certain supplements.
COMT adds a methyl group from SAMe to the dopamine, epinephrine, or norepinephrine molecules. This additional methyl group changes the original molecule into a different substance, which can be eliminated or recycled in the cells.
Drug and supplement metabolism:
COMT also breaks down some drugs used for asthma, Parkinson’s, and high blood pressure. It is also involved in metabolizing natural supplements like curcumin and quercetin.
Additionally, COMT is important in the phase II metabolism of estrogens. It converts estrogen metabolites into forms that can be excreted easily.
COMT Mutation and Altered Neurotransmitter levels
Several common genetic variants in the COMT gene alter how the enzyme functions. Some variants increase the speed at which the enzyme metabolizes neurotransmitters, and other variants can slow down the enzyme.
Terminology Explainer: The common variants that everyone looks at for COMT are technically polymorphisms (common changes in a gene) instead of mutations (rare changes). You’ll also see it referred to as a SNP, which stands for single nucleotide polymorphism.
The COMT enzyme is active in the prefrontal cortex, which is the brain region involved in planning, complex behaviors, and personality.
Researchers link COMT genetic variants to quite a variety of different diseases, from mood disorders to heart disease, possibly due to the COMT variants metabolizing neurotransmitters at different rates.
Psychiatric or mood disorders and COMT SNPs:
Some of the psychiatric disorders with increased risk associated with COMT genetic variants include:
The COMT variants do not cause these disorders alone. They simply add to the susceptibility.
Estrogen dominance and COMT:
COMT is also important outside of the realm of neurotransmitters. Since it also breaks down estrogens, there are differences in the amount of COMT available in the prefrontal cortex between males and females after puberty.[ref][ref]
For example, higher levels of estrogen can decrease COMT, leading to an increase in dopamine in female brains.[ref]
Is the Val158Met SNP “bad”?
One of the well-studied COMT genetic variants is known as Val1158Met or rs4680. This variant affects the speed at which the enzyme functions.
Also, known as COMT rs4680, the A/A or Met/Met variant is found in almost 20% of the population. The slightly more common G/G or Val/Val variant occurs in 35-40% of the population.[ref]
There is a lot written online about COMT – from Facebook groups to healthcare gurus selling supplements.
Often the information leads you to believe that carrying one of the other COMT rs4860 alleles is really bad! This simply isn’t true. Research shows there are both positive and negative effects of the variant.
Instead of one allele being bad and one being good (red or green, plus or minus), studies show these common variants just add to our uniqueness. I suggest looking at the various interactions between your genotype and supplements or lifestyle factors. Use your genetic information to optimize your health – mental and physical.
COMT Genotype Report
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COMT rs4680, Val158Met
Check your genetic data for rs4680 Val158Met (23andMe v4, v5; AncestryDNA):
- G/G: higher COMT activity (often called fast COMT or Val/Val)
- A/G: intermediate COMT activity (most common genotype)
- A/A: 40% lower COMT activity (often called slow COMT or Met/Met)
Members: Your genotype for rs4680 is —.
One of the most well-studied variants of the COMT gene is rs4680, often called Val158Met. In looking at research studies, the G is “Val” and the A allele is “Met”.
- The G allele (Val) has higher COMT enzymatic activity, causing a more rapid breakdown of the neurotransmitters and, thus, lower dopamine levels. In most populations, the G allele is the most common.[ref]
- The A allele (Met) has lower COMT enzyme activity and, thus, higher dopamine levels. This variant of the COMT enzyme is said to have lower activity because it breaks down faster at average body temperature.[ref]
Here are the findings from some studies on this COMT variant:
- People with the A/A genotype (met/met) have been shown to get more pleasure from pleasant events.[ref]
- However, people with the AA genotype, on average, may have more stress hormone release with stressful life events.[ref]
- A study of adults found that those with G/G genotype had lower neuroticism scores and higher agreeableness and conscientiousness scores than those with A/G or A/A.[ref]
- People with the A/A genotype may have a lower pain tolerance. A study of self-administered morphine in 973 patients following surgery found that the A allele was associated with higher morphine use. [ref]
- A small 2014 study looked at differences in fat oxidation and energy expenditure with green tea based on the COMT genotype. Those with the rs4680 G/G genotype had significantly increased energy expenditure and fat oxidation with green tea, while those with the A/A genotype had no increase.[ref]
- High activity COMT (rs4680 G/G) combined with MTHFR C677T T/T genotype is linked to higher homocysteine levels.[ref] High homocysteine is a risk factor for heart disease.
This common genetic variant also changes the activity level of COMT. The T allele is the less common version, with lower COMT enzyme activity; C is the more common version, with higher activity. This polymorphism is often inherited together with rs4680 in Caucasians[ref]
Check your genetic data for rs4633 H62H (23andMe v4, v5; AncestryDNA):
- C/C: higher (fast) COMT activity
- C/T: medium COMT activity
- T/T: lower (slow) COMT activity
Members: Your genotype for rs4633 is —.
Recent studies on this variant have found:
- Rs4633 T/T is associated with less back pain with lower back disk degeneration[ref][ref]
- A study of mercury exposure in children found that boys with the T/T 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 older Japanese population found the C/C genotype was associated with increased risk of atherosclerosis, especially in women.[ref]
- A study found that those with T/T had a higher risk of endometrial cancer.[ref]
Additional COMT Polymorphisms:
These variants can add to the effect of the main variants listed above.
Check your genetic data for rs6267 (23andMe v4, v5; AncestryDNA):
- G/G: typical
- G/T: risk of higher pain sensitivity[ref][ref]
- T/T: risk of higher pain sensitivity[ref][ref]
Members: Your genotype for rs6267 is —.
Methyl Donor Supplements:
Clinicians often suggest that those with the rs4680 A/A genotype (slow COMT) avoid going overboard with foods and supplements considered methyl donors. Methyl donors include methylcobalamin (methyl-B12), 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 subsequent fall in dopamine levels — causing mood swings, anger, or anxiety.
Related article specific to this topic: Supplement Interactions and COMT
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