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/

MAO-A Gene: An introduction

The MAO-A gene, popularly nicknamed the “warrior gene,” is responsible for the production of an enzyme monoamine oxidase A. (MAOA)

It breaks down monoamine neurotransmitters (dopamine, epinephrine, and serotonin) through oxidation.

Thus, mutations in the MAO-A gene can directly affect the levels of these neurotransmitters, which can potentially lead to various behavior-associated disorders.

Importance of MAOA

MAOA is an essential regulator of brain function and is highly expressed in the cells of the brain and heart. It mainly assists in the breakdown of neurotransmitters such as

Because MAOA regulates the level of these “behavioral-hormones,” too little or too much of this enzyme plays a role in a number of psychiatric and neurological disorders like schizophrenia and ADHD. In fact, a class of drugs that inhibit this enzyme (MAOA inhibitors) is prescribed to treat depression.

The Types of MAO-A Gene

All of us have the MAO-A gene, but we have different versions (or types or variants) of them. There are two types of MAO-A genes: a  high-activity (MAOA-H) and a low-activity (MAOA-L) type, based on the number of times the sequence of the gene is repeated. One of the most frequently studied variants is MAOA-4R, which has four repeats and is associated with a high-activity of the MAOA enzyme. Other alternate forms of the MAO-A variants, including the 2-repeat (2R) and 3-repeat (3R) versions.

Monoamine Oxidase Deficiency

The monoamine oxidase A deficiency follows an X-Linked inheritance pattern. Thus, this disorder is majorly seen affecting males.

Lower levels of this enzyme typically result in the buildup of neurotransmitters in the brain.

Various studies have linked this buildup with unusual behavioral patterns involving aggressive outbursts and abnormal sexual behavior. The deficiency of this enzyme has also been associated with abnormal brain development, which can directly lead to intellectual disabilities. There are also other variants of this gene that increase the enzyme levels. 

Lower levels of the enzyme result in a slower breakdown of the neurotransmitters - (Worriers), and higher levels of the enzyme lead to a faster breakdown - (Warriors). Both decreased and increased levels of the enzyme have various implications.

Increased Risk For Depressive And Bipolar Disorders

A study on around 18,000 people with psychiatric issues identified an SNP rs1137070 associated with major depressive disorder and schizophrenia. People with the T allele had higher enzyme levels and, as a result, lower levels of the neurotransmitters.

Another study found that the G allele of rs6323 had the highest expression of the MAOA enzyme. “Subjects with major depressive disorder with the highest activity form of the enzyme (G or G/G)”

Increased Risk For ADHD

A study identified an SNP rs3027407 on the MAO gene associated with ADHD. This SNP affects dopamine-mediating action, which is related to the symptoms of ADHD in children. A allele was found in higher frequencies in people with ADHD. 

Increased Risk For Aggression

T allele of rs909525 in the MAO gene is associated with less aggressive behavior due to the higher activity of MAOA - the warriors. The C allele is associated with more aggressive behavior.

Increased Expression for Anger

A variation in the MAOA gene was associated with higher levels of anger expressed outwards. The A allele of rs2064070 was associated with increased expression of anger. 

The study also found two other variants, rs909525 - C allele, rs6323 - G allele, associated with increased anger. 

Symptoms of MAOA Deficiency

Diet and MAOA

A study found that a poor quality diet during adolescence can affect the verbal ability of individuals who have a low expression variant of the MAO-A gene. People who ate vegetables very rarely and included more junk food in their diet had verbal deficits in early adulthood. 

The “psychopathic” personality traits were also observed more in subjects who frequently consumed fast foods during their adolescence - this was seen only in people with a low expression variant of the MAO-A gene. 

Diet Recommendations for People on MAOA Inhibitors

MAOA inhibitors (MAOA-I) are a class of drugs that lower the enzyme MAOA levels. Higher MAOA levels have been linked to conditions like depression.

When on MAOA-I, it is important to limit high-tyramine foods. Tyramine is an amino acid that helps regulate blood pressure. MAOA enzyme is required to break down tyramine, the buildup of which is associated with migraine headaches and life-threatening blood pressure spikes. 

So if you are on MAOA-I, it is important that you reduce your tyramine consumption.

Some foods high in tyramine are:

  1. Aged cheese
  2. Pickled fermented foods
  3. Soybeans
  4. Sauces
  5. Dried or overripe fruits
  6. Alcoholic beverages
  7. Fava beans

Summary

References:

  1. https://www.sciencedirect.com/topics/neuroscience/monoamine-oxidase-inhibitors
  2. https://en.wikipedia.org/wiki/X-linked_recessive_inheritance
  3. https://pubmed.ncbi.nlm.nih.gov/26227907/
  4. https://pubmed.ncbi.nlm.nih.gov/19593178/
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4093913/table/T3/
  6. https://www.snpedia.com/index.php/Rs909525
  7. https://pubmed.ncbi.nlm.nih.gov/23111930/
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