September 27, 2017

Are the COMT and MTHFR genes linked?

Two of the most talked about genes in relation to nutrigenomics and health are MTHFR and COMT. Indeed these two genes are frequently discussed together by individuals and healthcare professionals (R). Partly this is because of well investigated and characterized polymorphisms such as C667T for MTHFR, or G472A for COMT, with described health impacts, but also because the frequency of their occurrence in the population is relatively high.

In this post I’m going to do a brief run through of each genes function which will then lead into a discussion about how they may both be linked.


I’ve covered Methylene tetrahydrofolate reductase or MTHFR before in quite a bit of depth so I think we only need a short refresher here, but if you’d like to know more check out this post, or the MTHFR gene page.

So, MTHFR is an enzyme which is encoded for by the MTHFR gene, its major function is to convert 5,10-methylenetetrahydrofolate (MeTHF) to 5-methlytetrahydrofolate (MTHF) (R). On its own this reaction doesn’t sound very inspiring, but alterations in MTHFR activity can have profound effects throughout the body including increased cardiovascular risks (R), various neurological issues (R) and also issues during pregnancy (R).

Borrowing the diagram from that previous post you can see that MTHFR sits in the one carbon pathway which takes in dietary folate and then cycles it through various forms, a key step occurring when MTHF is converted back into THF (losing a methyl group) when methionine synthase converts homocysteine into methionine.

Briefly dietary folate is converted into tetrahydrofolate (THF) as an entrance point into the one carbon cycle. SHMT1 converts THF into 5,10-methylenetetrahydrofolate (5,10-MTHF). 5,10-MTHF is then converted into 5-MTHF via MTHFR. Finally methionine synthase uses 5-MTHF as a methyl donor to convert homocysteine into methionine, resulting in the reformation of THF.

Polymorphisms in MTHFR lead to a lack of 5-MTHF which stalls methionine synthase activity. This stalling leads to the accumulation of homocysteine and a reduction in the levels of methionine.

Homocysteine is the bad guy in this picture, although it is required for good health, when its levels in the body get too high it leads to the health issues discussed above. If you look at where MTHFR sits in the pathway, you can quickly see how reductions in its activity could lead to the accumulation of homocysteine. As less MTHF is produced less is available for methionine synthase to use in the conversion of homocysteine into methionine, in effect the various cycles stall.

The two SNPs shown for MTHFR, C677T and A1298C have been shown to reduce MTHFR activity and thus lead to homocysteine accumulation (R).

However, it is also clear that when the levels of homocysteine are increased, the levels of methionine are reduced, and this is where COMT comes in.

ProteinGeneSNP IDMajor Allele/Minor Allele (Risk)Risk
C/TC (Ala) > T (Val) leads to a heat-sensitive enzyme with reduced activity. Also the required co-factor vitamin B2 is released more quickly by those with the ‘T’ allele [R].
A/CA (Glu) > C (Ala) leads to a smaller reduction of enzyme activity than described above through an unknown mechanism [R].


Catechol-O-methyltransferase or COMT is an enzyme encoded for by the COMT gene which functions to inactivate neurotransmitters such as dopamine (RR).

Neurotransmitters are small molecules which the body uses to transmit nerve impulses between cells in order to induce an effect. These are usually quite rapid events and so neurotransmitters are usually inactivated very quickly.

COMT is one of many enzymes which inactivates neurotransmitters, functioning by attaching a methyl group into their structure, which is donated by S-adenosyl methionine (SAM-e). You can probably see where this is going, but I’ve included a figure below to make it clear.

SAM-e production is influenced by the methionine cycle, which involves the conversion of homocysteine into methionine. This methionine is then converted into SAM-e which is widely used throughout the body as a methyl donor, with COMT being a major user. If SAM-e production is reduced then so too is COMT activity which has been associated with several poor health outcomes.

Methionine formed by methionine synthase (or BHMT) is converted into SAM-e, which is widely used throughout the body as a methyl donor. 

However, COMT doesn’t just have to be a bystander in this process as it features polymorphisms in its own right. G472A (R) is the most well-established SNP and is often shown alongside C186T. However, it is important to note that C186T does not have any impact on COMT activity itself, rather it is a commonly used marker for G472A with ‘C’ mapping to ‘G’ and ‘T’ mapping to ‘A’ (R).

ProteinGeneSNP IDMajor Allele/Minor Allele (Risk)Risk
G/AG (Val) > A (Met) leads to a 75% reduction in COMT activity [R].
C/TC and T act as markers for G472A status. With C associating with G, and T associating with A.

Interestingly both the ‘G’ and ‘A’ alleles can be considered risk alleles. Therefore those carrying two copies of the ‘A’ allele show reduced COMT activity which is associated with increased dopamine levels in the brain. This is thought to lead to a lower pain threshold (R) and increased stress sensitivity (R) but improved memory and attention to detail (R). Carriers are therefore sometimes termed ‘Worriers’ (R).

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 (R) and capacity to deal with stress (R), at the expense of a reduction in cognitive performance in non-stressful environments. Therefore, carriers of two ‘G’ alleles are sometimes termed ‘Warriors’ (R).

As we’re specifically looking at MTHFR and COMT here we should consider the ‘A’ allele as the risk, as this is the form associated with reduced activity.

Are COMT and MTHFR linked functionally?

From all the above it’s pretty clear that COMT and MTHFR activity are linked, and by combining the two pathways together we can see how they can impact on each other. I discuss mechanisms to target these further down in the post.

Combining everything together we can clearly see how MTHFR can impact on the formation of methionine and thus SAM-e, which in turn limits COMT activity.

However, interpreting the interaction of multiple enzymes and polymorphisms can be a tricky business.

Are COMT and MTHFR linked genetically?

So COMT and MTHFR are linked functionally, how about at the genetic level. One of the more complex ideas of genetics is linkage disequilibrium. This describes when two separate regions of the genome more or less often than would be expected by chance.

Only a single study has been performed looking at this which suggested that there was no significant link between the two, at the genetic level, however the authors note that this was performed on a small population with a larger study required. This suggests that your MTHFR status and your COMT status are likely to be independent of each other (R).

Can I target COMT or MTHFR?

Lets quickly run through a couple of potential interactions and see what the outcomes would be:

  • If MTHFR activity is reduced but COMT activity is normal, then COMT will still be impaired as it will have less SAM-e to work with, homocysteine levels will also be increased. Targeting homocysteine accumulation by encouraging MTHFR (vitamin B2 (R)) or methionine synthase (vitamin B12 (R)) activity should therefore also benefit COMT activity.
  • If MTHFR activity is normal but COMT activity is reduced, then the health outcomes associated with COMT will be observed, but homocysteine levels will likely be normal so no effect should occur. In this instance targeting COMT directly (vitamin B6 and magnesium (R,R)) should prove beneficial.
  • If the activity of both is reduced then things become more difficult, a reduction in SAM-e and accumulation of homocysteine will occur with potentially more serious health impacts. In this instance a panel of B vitamins might prove most beneficial however modulating the various interactions and dosing levels can be difficult.

The exact mechanisms of each of these nutrients are covered on the MTHFR and COMT gene pages respectively if you’d like to know more detail about their activity.

Take home message

While COMT and MTHFR are linked functionally, with MTHFR in particular able to exert a large effect on COMT activity, they do not appear to be linked genetically. However, as C677T and A1298C in MTHFR and G472A in COMT are common polymorphisms observing people with one or multiple SNPs is highly likely.

Direct targeting of polymorphisms is relatively straightforward however when multiple polymorphisms and genes interact these interventions become much more complicated.

See also: Our Guide to Nutrigenomics

Aaron Gardner

Dr Aaron Gardner is a life-scientist with a strong background in genetics and medical research, and a particular interest in the developing fields of personalised medicine and nutrition.

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