The COMT V158M Gene's (rs4680) Effects
COMT breaks down dopamine mostly in the part of the brain responsible for higher cognitive or executive function (prefrontal cortex). (R)
COMT and Methylation
Catechol- O -Methyltransferase is an enzyme that transfers methyl groups (hence the name methyltransferase).
Having too little SAM (s-adenosylmethionine) and too much SAH (s-adenosylhomocysteine) from undermethylation results in COMT inhibition as well (R).
For this reason, having MTHFR SNPs that cause undermethylation and COMT SNPs that result in lower COMT are a bad combination.
COMT gene production is itself influenced by methylation (R). Usually, methylation shuts down gene production.
Reactions By COMT
Specific reactions catalyzed by COMT include:
- Dopamine → 3-Methoxytyramine
- DOPAC → HVA (homovanillic acid)
- Norepinephrine → Normetanephrine
- Epinephrine → Metanephrine
- Dihydroxyphenylethylene glycol (DOPEG) → Methoxyhydroxyphenylglycol (MOPEG)
- 3,4-Dihydroxymandelic acid (DOMA) → Vanillylmandelic acid (VMA)
Catechol Estrogens, Cancer and Autoimmunity
Catechol estrogens form from CYP enzymes breaking down Estradiol and Estrones.
Catechol estrogens can break DNA and cause cancer and autoimmune conditions.
COMT methylates (using SAM) and inactivates these catechol estrogens (2- and 4-hydroxycatechols).
The products of COMT methylation are 2- and 4-o-methyl ethers, which are less harmful and excreted in the urine (they have anti-estrogen properties).
However, if COMT is inhibited too much either because of genetics or dietary inhibition, it should result in higher levels of catechol estrogens, especially if glucuronidation and sulphation pathways are not working.
4-Hydroxyestrone/estradiol was found to be carcinogenic in the male Syrian golden hamster kidney tumor model, whereas 2-hydroxylated metabolites were without activity.
4-Hydroxyestrogen can be oxidized to quinone intermediates that react with purine base of DNA, resulting in depurinating adduct that generates cancerous mutations. Quinones derived from 2-hydroxyestrogens are less toxic to our DNA (R).
Estrone and estradiol are oxidized to a lesser amount to 2-hydroxycatechols by CYP3A4 in the liver and by CYP1A in extrahepatic tissues or to 4-hydroxycatechols by CYP1B1 in extrahepatic sites, with the 2-hydroxycatechol being formed to a larger extent (R).
It has been observed that tissue concentrations of 4-hydroxyestradiol are highest in malignant cancer tissue, out of all the estrogens (R).
Catechol Estrogens have potent endocrine effects and play an important role in hormonal regulation (those produced by hypothalamus and pituitary) (R).
Increased availability of estrogen and estradiol for binding and hypothalamic sites would facilitate the formation of Catechol Estrogens. These estrogens affect Luteinizing Hormone (LH) and maybe follicle stimulating hormone (FSH) and prolactin (R).
Catecholestradiol competes with estradiol for estrogen binding sites in the anterior pituitary gland and hypothalamus and dopamine binding sites on anterior pituitary membranes (R).
Other possible mechanisms of inactivation of these catechol estrogens include conjugation by glucuronidation and sulphation (R).
High concentration of 4-hydroxylated metabolites caused insufficient production of methyl, glucuronide or sulfate conjugate which in turn results in catechol estrogen toxicity in cells and oxidation to semiquinone and quinone, which may reduce glutathione (GSH). These oxidation products could lead to DNA mutations (R).
The quinone/semiquinone redox system produces superoxide ions (O2¯ ) which can react with NO to form peroxynitrite, which could cause DNA damage (R).
In summary, CEs lead to the production of potent ROS, capable of causing DNA damage, thus playing an important role not only in causing cancer but also in systemic lupus erythematosus (SLE) and Rheumatoid Arthritis (R).
The abilities of the estrogens to induce DNA mutations were ranked as follows:
4-hydroxyestrone (most damaging) > 2-hydroxyestrone > 4-hydroxyestradiol >2-hydroxyestradiol > > Estradiol, Estrone (R).
Supplements and COMT
Any compound having a catechol structure, like catechol estrogens and catechol-containing flavonoids, are targets of COMT (R) and are also capable of inhibiting enzyme function (either directly or through competition) (R).
Such flavanoids that are modified by COMT and also inhibit/compete with COMT include Quercetin (R, R), Rutin, Luteolin (R), EGCG (R), Catechins, Epicatechins, Fisetin (R), Ferulic acid, and Hydroxytyrosol (R, R2).
The following flavanoids don’t have the catechol structure: apigenin (R), genistein, chrysin, myricetin (R), and flavones (includes apigenin, tangeritin, chrysin, baicalein, scutellarein, wogonin) (R).
Intro to COMT V158M (rs4680)
This is one of the most researched SNPs because it plays an important role in intelligence, personality and disease risk.
This gene variant has been found to affect executive functions such as cognitive flexibility, impulse control, abstract thought, and being able to follow rules or task structure. (R)
If you have AA then you will have the highest dopamine, while GG results in the lowest dopamine. AG is somewhere in the middle.
Either too little or too much Dopamine can decrease cognitive performance (R).
Under stress, dopamine increases. High dopamine producers (AA) will perform worse under stress because they will have too much dopamine. Low dopamine producers (GG) will perform better because now they’ll have an optimal level.
Most of the research involves AA and GG because you can find more statistically significant differences between these.
People with AG have COMT levels that are midway between that of AA and GG (R).
References: COMT and executive function.
COMT and Gender Effects
COMT is decreased by estrogen (R), such that overall COMT activity in prefrontal cortex and other tissues is about 30% lower in females than in males (R). This diminished COMT activity translates to about 30% higher baseline Dopamine levels in females than males (R).
Females have near optimal levels of baseline dopamine levels, but males having somewhat too low baseline dopamine, such that male performance improves when dopamine levels are slightly increased, whereas female performance does not.
Therefore, having SNPs that result in lower COMT (such as the A allele for rs4680) will be more helpful for males, but not females. Indeed, males with lower COMT do, in fact, demonstrate improved performance on tasks dependent on the prefrontal cortex, whereas females do not (R).
COMT and 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
Interestingly, the AG group tended to have the best IQ (both verbal and performance IQ) and best scores overall, though most weren’t statistically significant.
AA and AG had superior performance relative to GG on reading-related skills (PA, Spelling), and marginally better performance for Decoding but not on more general language skills (Oral Language, Comprehension) or IQ. (R) Various groups showed more activation in different regions of the brain. The AA group showed the most activation in areas responsible for reading comprehension (frontal lobe) and these were the best readers, overall.
Performance IQ (PIQ)+Verbal IQ (VIQ)= Total IQ
COMT and Personality
The lower dopamine producers (GG) were more extroverted and less neurotic.
- Met/Met=AA; High dopamine in prefrontal cortex.
- Val/Val= GG; Lower dopamine in prefrontal cortex.
The Worrier (A)…Lower COMT, Higher Dopamine. (Met)
AA is considered the ‘risk’ or ‘bad’ allele in part because people don’t do well with stress and because lower COMT can create issues with methylation and not breaking down estrogen byproducts (catechol estrogens).
AA’s get more pleasure out of life but also more misery (bigger high’s and low’s).
- Gets more pleasure out of life – AA’s had twice the positive emotion towards a pleasant event than GG’s. GG people subjectively viewed a very pleasurable event on the same level that AA would view a slightly pleasurable event. AG had a mid-level effect for this was “quite large”. (R)
- More Creative (divergent thinking fluency – more of an effect with other genes). Dopamine in the Prefrontal cortex promotes cognitive stability by being more resistant to distractions. (R)
- Higher IQ (tested in people with schizophrenia). (R)
- Better working memory. (R, R2) – during an N-back task and a go-no-go task, there was increased activation in the right posterior cingulate cortex for healthy adults with AG and AA compared to GG. (R) Also, better verbal working memory(letter-number sequencing) in AA and AG compared to GG. (R)
- Better reading comprehension (R)
- More plasticity in older age – better responses to N-back brain training. (R)
- Better cognitive function when not under stress: Better attention and processing of information (executive function). (R) However, realize that this one gene only accounts for 4% of the difference in executive function. The FAB exam tests executive function. GG scored an average of 16.0, GA 15.7 and AA 15.3. These scores are statistically significant, but not large.
- More Exploratory (R)
- Have a better response to placebos. (R) – Dopamine is thought to link to reward and ‘confirmation bias’ which enhance the sense that the treatment is working. More prominent in studies with subjective conditions such as pain and fatigue rather than objective physiological measurements. The response of patients with AG fell in the middle.
- Higher cognitive stability? but comparatively low
cognitive flexibility. (R)
- Increased verbal fluency for males (but decreased it for females). (R)
- Better fine motor skills(AA vs GG) (control of small muscles in the fingers for grasping and manipulation). (R)
- Better ability to Aim. (R)
- AA’s focus more when they realize they have made an error.
- Better absorption of tea polyphenols/EGCG. (R)
- AA’s had a lower risk for alcoholism. (R)
- AA’s had a better response to Paxil/paroxetine. (R)
- Worse handling of stress or pain. Researchers found when viewing unpleasant pictures, the startle response of women with AA was about six times stronger compared to those with only one A or none at all. (R)
- Anxiety: Studies have correlated AA allele with OCD, panic disorder, phobic anxiety. (R, R2)
- Lower emotional resilience/more negative emotions/less able to handle negative events well.
- More impulsive (AA vs GG). (R) More significant in people who had AA for this gene AND TT for rs6313. (R)
- More depression – but the relationship is complex. (R)
- Less Cooperative, Helpful and Empathic (AA, in females) (R)
- Less Extroverted (R)
- More neurotic (trended). (R)
- Higher Homocysteine – 10.4% in AA. [R]
- Higher risk of ADHD and ADHD severity (R)
- Higher sensitivity to mercury – boys (but not girls) with AA had impaired cognitive performance when exposed to mercury. (R)
- Fibromyalgia people with AA showed higher sensitivity to heat and pressure pain stimuli (R)
- It has also been linked with breast cancer risk — Asian-American women who have an AA or one A who also drink black or green tea appear to have a decreased chance of developing the disease. (R)
- 44% Increased risk for cocaine dependence. [R]
- boys with TT had worse cognitive performance when acutely exposed to mercury. (R)
The Warrior (G)…Higher COMT, Lower Dopamine (Val)
- Better handling of stress and pain. [R]
- Better at learning languages. (R)
- More Cooperative, Helpful and Empathic (GG, in females) (R)
- Higher emotional resilience/able to handle negative events well. [R]
- Increased verbal fluency for females (also decreased for males). (R)
- Better working memory and higher hippocampal volume – in healthy Chinese. (R) As you can see AA is not always smarter than GG and it depends on other factors.
- GG deprived of sleep responded well to modafinil in terms of improved vigor, well-being, and maintained baseline performance with respect to executive functioning. AA individuals barely responded to the drug at all. [R]
- Can more easily get into hypnosis. [R]
- GG results in more methylation in the gut (R).
- Less pleasure out of life – AA’s had twice the positive emotion towards an event than GG’s. GG people subjectively viewed a very pleasurable event on the same level that AA would view a slightly pleasurable event.
- Lower IQ (tested in people with schizophrenia) (R)
- Worse executive function/processing information, but better under stress. However, realize that this one gene only accounts for not more than 4% of the difference in executive function. The FAB exam tests executive function. GG scored an average of 16.0, GA 15.7 and AA 15.3. These scores are statistically significant, but not large. [R]
- Worse fine motor skills (AA vs GG) (control of small muscles in the fingers for grasping and manipulation). (R)
- Less Exploratory (R)
- More childhood depressive symptoms for GG. (R)
- 2X increased risk for breast cancer. (R)
- GG has 11X Higher risk of getting schizophreniform disorder from smoking pot as a teenager. AG has a 2.5X likelihood. However, a later study did not find this. (R)
- Increased risk for endometrial cancer.
G alleles had a worse response to Paxil/paroxetine.
G allele frequencies: East Asians have 71% G’s, Africans 69% G’s Americans 61% G’s, Europeans 48% G’s (R). So East Asians are going to be more likely to have GG vs Europeans.
Other COMT Genes
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. (R)
Fixes For Low COMT
If you have lower levels of COMT, you should take/do the following:
- SAM-e – however, this can increase dopamine levels in people who already have high dopamine.
- Adequate B6, B12, folate, and betaine to support formation of S-adenosylmethionine and prevent elevated homocysteine; S-adenosylhomocysteine inhibits COMT activity (R).
- DIM if you have high estrogens because estrogens inhibit COMT (R) and also because these estrogens can cause cancer – especially breast cancer.
- Ensure adequate anti-oxidants to prevent oxidation of dopamine and pro-carcinogenic 4-hydroxyestrogens,
- Magnesium (magnesium is a cofactor)
- Be careful of the following supplements that are the targets of COMT: quercetin, rutin, luteolin, EGCG, catechins, Epicatechins, Fisetin, Ferulic acid, Hydroxytyrosol
- Avoid excessive alcohol consumption. Since alcohol-induced euphoria is associated with the rapid release of dopamine in limbic areas, low activity COMT variant would have a relatively low dopamine inactivation rate, and therefore would be more vulnerable to the development of alcohol dependence (R).
- Avoid stimulants, especially amphetamines. Amphetamines may do worse with people who are AA, but later studies did not replicate this. It could be differences in study design (R).
- Avoid chronic stress (stress hormones require COMT for degradation and compete with estrogens),
Stay away from COMT inhibitors, which include:
Mercury is also a COMT inhibitor (R), so make sure you reduce your load or take supplements that bind to mercury.
Fixes For Higher COMT
If you have higher COMT levels:
- Deprenyl to increase dopamine,
- Mucuna to increase dopamine,
- Tyrosine to increase dopamine,
- EGCG/Tea (COMT inhibitor),
- Epicatechins/Chocolate (COMT inhibitor),
- Luteolin (COMT inhibitor),
- Fisetin (COMT inhibitor),
- Rutin (COMT inhibitor),
- Quercetin (COMT inhibitor),
- Ferulic Acid (COMT inhibitor),
- Hydroxytyrosol (COMT inhibitor),
Advanced Fixes For High COMT
These are not recommended without serious thought and a doctor’s guidance: