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COMT Gene

The COMT gene is responsible for producing an enzyme called catechol-O-methyltransferase. This enzyme helps in the breakdown of catecholamines, thereby inactivating them. Catecholamines, termed as fight or flight hormones, include dopamine, epinephrine, and norepinephrine. They are produced in response to stress. They are responsible for increasing heart rate, blood pressure, breathing rate, muscle strength, and alertness. They also play a role in increasing blood flow to major organs like the brain, heart, and kidneys.

COMT is one of the enzymes involved in the breakdown of dopamine in the brain. This occurs in the prefrontal cortex of the brain. This part of the brain is involved in cognitive function and decision making. 

The COMT Variants

COMT gene comes in two main variants - one that breaks down dopamine quickly and the other one that breaks it down slowly. 

What does this mean?

One variant produces high levels of the enzyme, which breaks down dopamine faster, leading to its lower levels in the brain.

The other variant produces lower levels of the enzyme, which results in slower breakdown of dopamine, resulting in its higher levels in the brain.

rs4680 SNP

The COMT gene variants are influenced by the allele present at rs4680. 

rs4680, also called Val158Met, is a well studied SNP in the COMT  gene.

The G allele here is associated with higher COMT enzymatic levels compared to the A allele. 

The presence of two A alleles at rs4680 results in lower enzyme activity. This leads to dopamine build-up in the brain. People with the AA type are more susceptible to stress, anxiety, and pain and are called “worriers.”

The presence of two G alleles at rs4680 leads to elevated enzymatic levels. This results in faster breakdown of dopamine. People with the GG type clear dopamine quickly at times of stress and can fight it out better. They are referred to as the “warrior.”

There’s also a third and much less discussed variant. Here, there’s one copy of the A allele and one copy of the G allele at rs4680. People with the AG type have higher dopamine levels than the AA type and lower levels than the GG type.

They are assigned a status that’s between a worrier and a warrior. The outcome of AG genotype can be as follows:

A higher likelihood of warrior personality (compared to AA type);

A higher likelihood of worrier personality (compared to GG type)

GenotypeImplication
AAHigher levels of dopamine
AGIntermediate levels of dopamine (lower than AA genotype and higher than GG genotype) 
GGLow levels of dopamine
COMT gene allele variations

Despite the negative connotation to the word “worriers,” these people are at certain advantages as well. They are known to be: 

- more creative 

- have higher IQ

- better motor skills

- better verbal memory and reading comprehension

- a more positive outlook towards life

Boosting Dopamine Levels Naturally

Dopamine promotes the feeling of pleasure and reward, which can help with better attention and memory. Some ways of boosting dopamine levels include:

- Increasing protein intake

- Consuming probiotics

- Exercising

- Enough sunlight exposure

- Getting adequate sleep

Counteracting Excess Dopamine

Higher dopamine levels have been associated with addiction and mental disorders like ADHD, obsessive-compulsive disorder, and schizophrenia. The “reward” feeling elicited by dopamine makes you want ‘more of something.’ When the levels of dopamine are higher than normal, this behavior can result in addiction. 

- Inhaling lemon essential oil speeds up the breakdown of dopamine and contributes to anti-anxiety and antidepressant effects.

- Tryptophan and 5-HTP are two amino acids that deplete excess dopamine. They are available as supplements. However, it is important to consult a qualified medical practitioner before getting started on any supplements.  

- Licorice root, a common ingredient in candies, is being studied for its antidotal properties for cocaine addiction, as it blocks dopamine production. However, the US FDA mentions that licorice containing food must be consumed in moderation. 

- Vitamin B6 is a cofactor required for dopamine synthesis. Dopamine toxicity has been managed in animals by vitamin B6 administration

Summary 

1. COMT gene encodes the enzyme catechol-O-methyltransferase that is involved in the metabolism of catecholamines like dopamine, epinephrine, and norepinephrine. 

2. COMT gene has two variants - one that breaks down dopamine quickly, and the other that breaks it down slowly.

3. rs4680, also known as Val158Met, is an SNP in the COMT gene. The G allele of this SNP is associated with higher enzymatic levels compared to the A allele. 

4. People with AA type have higher levels of dopamine. They don’t perform well under stress and are called worriers. People with the GG type have lower dopamine levels. They perform better in stressful situations and are called warriors.

5. The third type, AG, is associated with intermediate dopamine levels. People with the AG type are assigned a status that is between a worrier and a warrior.

6. Levels of dopamine can be increased naturally by getting adequate sleep, exercising, sunlight exposure, consuming probiotics, and more protein.

7. Inhaling lemon essential oil, consumption of licorice root, and other supplements can help deal with high dopamine levels. 

References

1. https://www.snpedia.com/index.php/Rs4680

2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991696/

3. https://pubmed.ncbi.nlm.nih.gov/24782743/

4. https://pubmed.ncbi.nlm.nih.gov/24853458/

5. https://pubmed.ncbi.nlm.nih.gov/24225542/

6. http://www.haskins.yale.edu/Reprints/HL1712.pdf

7. https://pubmed.ncbi.nlm.nih.gov/17687265/

8. https://pubmed.ncbi.nlm.nih.gov/16780969/

9. https://www.sciencedaily.com/releases/2009/02/090218223504.htm

10. https://pubmed.ncbi.nlm.nih.gov/2035239/

The COMT gene codes for the production of catechol - O -Methyltransferase enzyme. This enzyme is associated with degrading neurotransmitters, transfering methyl groups to epinephrine, norepinephrine and dopamine ( catecholamines).  

 

COMT Gene

By uploading DNA raw data from 23andme COMT gene variant carried may be determined ,which can also be used to identify tendency for specific personality traits. 

 

The COMT enzyme is also associated with the breakdown of certain drugs prescribed for hypertension, Parkinson’s disease and asthma.

Function of COMT gene variant


The following processes are associated with the COMT variant under study.

Catechol estrogens- role in cancer

The catechol estrogens are associated with hormone regulation and can have a potent endocrine effect. The hormones that may be affected by these catechol estrogens include prolactin, luteinizing hormone and follicle stimulating hormone.

Estrogens are known to lead to cancer by encouraging proliferation of cells and resulting in damage. These hormones are found to be highly mitogenic, especially in sensitive tissues like breast and uterus. When such sensitive tissues are exposed to such mitogenic stimulation for a prolonged period of time, it is found to lead to cancer.

Estradiols are found to cause DNA damage (sister chromatid exchange and chromosomal aberrations). Such genotoxic effects are also produced by catechol estrogens

Mechanism of conversion to Catechol estrogens:

In the liver, CYP3A4 oxidises estrone and estradiol to 2-hydroxycatechols and by CYP1A in extrahepatic tissues. In extrahepatic sites, CYP1B1 oxidises estrone and estradiol to 4-hydroxycatechols.


The concentration of 4-hydroxyestradiol is found to be the highest in cancerous tissues when compared with the different types of estrogens. In the hypothalamus and in the pituitary glands, the concentration of catechol estrogens is found to be 10 times more than the parent estrogens.

 

Studies have also shown that catechol estrogens have a more carcinogenic effect on mice than estradiol. These catechol estradiols compete with estradiol for binding to

 

23andme COMT Variant in lowering Cancer risk:

 

The Catechol estrogens that are known to affect DNA and result in cancer or autoimmune conditions are converted into methoxy estrogens.

2- and 4-o-methylethers, products of COMT, are excreted in the urine and are found to be less harmful.  


Using the DNA raw data of  23andme COMT gene variant carried by an individual can be used to identify the level of inhibition of COMT. Increased inhibition could lead to increased levels of catechol estrogens.

The reactive oxygen species produced by the catechol estrogens not only increases risk of cancer but also for other autoimmune conditions like rheumatoid arthritis and systemic lupus erythematosus.


COMT rs4680 (Val158Met)

 

This variant of the COMT gene is well studied and is associated with warrior/ worrier personality (personality), pain tolerance(fitness) and in cocaine dependence (Substance dependence) and disease risk (Health)


rs4680- The wild type allele codes for valine while the A allele codes for methionine. This change in amino acid results in nearly 25% reduction in enzyme activity. This results in increased dopamine among A allele carriers.

 

Upload your 23andme raw data or your Ancestry DNA raw data to find the variant of rs4680 that you carry

GenotypePhenotype
GGMore likely to have higher enzyme activity and lower dopamine level
GAModerate enzyme activity and moderate dopamine level
AAMore likely to have lower enzyme activity and higher dopamine level


COMT gene and personality

A study conducted to identify the effect of this COMT variant showed that Valine carriers have better prefrontal hyperactivation and were better at responding to adverse stimuli. These individuals was classified by the researchers as having warrior personality. The met allele carriers had better memory and an advantage in attention tasks. These individuals were termed worriers by the researchers, providing a way to identify warrior and worrier personalities.

 

By uploading Raw data from 23andme COMT variant carried can be used to identify certain other personality traits as well- A study conducted in 2015 on  normal adults showed that people who carried specific variant of this COMT gene scored lower on neuroticism while they had higher scores for conscientiousness and agreeableness.  

 

Xcode Personality report provides information on genetic tendency for certain personality traits, including warrior and worrier personality, and the big 5 personality traits.

 

COMT gene and Disease risk


COMT variant is important in identifying the risk for schizophrenia. A study conducted in 2016 showed that the COMT gene variant was associated with negative symptoms of schizophrenia and bipolar disorder.

Xcode health report includes susceptibility for more than 45 diseases, including schizophrenia.

COMT gene and Cocaine dependence

The COMT variant is known to influence prefrontal cortex (PFC) dopamine regulation which has been associated with cognition and personality. However, PFC dysfunction is also important in cocaine dependence, which could contribute to loss of control and, thereby, dependence. This variant has also been implicated for other substance abuse.

Xcode Substance dependency report includes risk of dependency for many substances including cocaine, cannabis, heroin, alcohol and nicotine.

 

COMT gene and Pain

In a study conducted by researchers from The University of Michigan, COMT variant was associated with the intensity of pain.

Effect of gender on COMT gene variant


The activity of COMT enzyme is about 305 lower among females as it is decreased by the presence of estrogen. This results in greater dopamine activity in females than in males. Therefore men benefit from increasing their dopamine levels than females.

COMT gene variant and supplements

Studying DNA raw data from 23andme will help in identifying individuals who have low COMT enzyme activity and who have higher levels of dopamine, which can eventually build up . However, consumption of certain methyl donor supplements can result in a fall in dopamine levels that can lead to mood swings.  

Some supplements include

COMT and MTHFR


The COMT enzyme plays a role in methylation. Individuals who carry genetic variants associated with lower MTHFR enzyme and genetic variants associated with lower COMT enzyme will be more prone to the effects of stress.

 

DNA raw data from 23andme and other genetic testing services can be used to identify varied risks and benefit based on the COMT variant carried by an individual. Select from the list of Xcode reports available to help tailor lifestyle based on the genetic variant carried.

References:

  1. https://en.wikipedia.org/wiki/Catechol_estrogen
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583214/
  3. https://www.ncbi.nlm.nih.gov/pubmed/12595695

 

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