Catechol-O-methyltransferase (COMT) is an enzyme which inactivates neurotransmitters such as dopamine and epinephrine, and is encoded for by the COMT gene 1.

Neurotransmitters are small molecules used to transmit nerve signals between nerve cells, or from a nerve cell to a target cell, such as a muscle cell. Neurotransmitters bind to receptors on the surface of target cells to induce their effect, and then are typically rapidly degraded in order to “turn off” their activity. As an enzyme, COMT can inactivate numerous neurotransmitters including dopamine, epinephrine and norepinephrine 2.

COMT deactivates these neurotransmitters by introducing a methyl group into their structure, which is donated by S-adenosyl methionine (SAM) 2. SAM production is influenced by the methionine cycle in which the methylenetetrahydrofolate reductase (MTHFR) enzyme is the limiting step. Therefore it is common for COMT and MTHFR to be talked about simultaneously 3.

There is one SNP within the COMT gene associated with poor health outcomes rs4680 or G472A.

Risk Description
Both the ‘G’ and ‘A’ allele of G472A in the COMT gene are associated with neurological characteristics associated with altered COMT activity 4. The COMT enzyme formed from the minor ‘A’ allele has been reported as having approximately a 75% reduction in activity compared to those formed from the major ‘G’ allele 5.

Therefore those carrying two copies of the ‘A’ allele display lower COMT activity which is associated with increased dopamine levels in the brain. This is thought to lead to a lower pain threshold 6 and increased stress sensitivity 7 but improved memory and attention to detail 7, a potential risk for Parkinsons disease 8 has also been described. Carriers are therefore sometimes termed ‘Worriers’ 9.

Conversely those carrying two copies of the ‘G’ allele display higher COMT activity which is associated with decreased dopamine levels in the brain. This increased activity is thought to lead to a higher pain threshold 6 and capacity to deal with stress 7, at the expense of a reduction in cognitive performance in non-stressful environments. Therefore, carriers of two ‘G’ alleles are sometimes termed ‘Warriors’ 9.

Outside of neurological conditions the ‘A’ allele, which is associated with low activity, is linked with increases in the potentially harmful homocysteine 10; often associated with an elevated cardiovascular risk 11. As the ‘A’ allele form of COMT displays reduced methylation activity its methyl donor source (methionine) builds up. Methionine is typically formed by the processing of homocysteine using either methionine synthase (MTR) or betaine homocysteine methyltransferase (BHMT). Typically methionine is rapidly used, however when it accumulates it blocks further MTR or BHMT activity leading to a homocysteine accumulation.

However, it is important to note that the interaction between genetics and behaviour is very complex. While alterations in COMT activity undoubtedly have an effect there are many other factors which influence our behaviour 12.

Direct Nutrients:*
Ingredient Active Ingredient Effect
Magnesium is a cofactor for COMT, required for its efficient activity 13.

Those carrying two copies of the ‘A’ allele of G472A, which is associated with a significant reduction in COMT activity may therefore benefit from magnesium supplementation. Whilst no studies have directly assessed the impact on magnesium on those carrying two copies of the ‘A’ allele a general anti-depressive effect has been described 14.

As magnesium is vital for a wide variety of functions it is not recommended for those carrying the ‘G’ allele to try and reduce magnesium intake.

Vitamin B6 Pyridoxal phosphate
The ‘A’ allele of G472A is associated with an accumulation of homocysteine 10, potentially driven by inhibition of MTR and BHMT activity caused by a buildup of methionine.

Along with MTR and BHMT there is an alternative pathway to clear homocysteine using cystathionine β synthase (CBS) and cystathionine γ ligase (CTH). As opposed to MTR and BHMT which form methionine, CBS and CTH form cysteine, and so should not be limited by methionine accumulation.

Both of these enzymes use vitamin B6 as a cofactor, in the absence of vitamin B6 the activity of both enzymes is reduced 15.

Therefore those carrying the ‘A’ allele may benefit from vitamin B6 supplementation to ensure maximal CBS and CTH activity.
Risk Description
C186T is often reference as an independent driver of poor health outcome. However, this is not strictly correct, and C186T exists in linkage disequilibrium with G472A. Simply put the ‘C’ allele of C186T is always present when the ‘G’ allele of G472A is. Similarly the ‘T’ allele of C186T is always present when the ‘A’ allele of G472A is. This close linkage can be observed in the identical minor allele frequency (47%) associated with each SNP 16.

C186T was often therefore used as a proxy for G472A due to difficulties with its analysis. However, modern consumer genetic testing kits are able to accurately differentiate between G472A allele making assessment of C186T redundant.

Discuss this information with your doctor before taking any course of action.

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