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COMT

Can This Gene Influence Your Risk of Schizophrenia (COMT)?

Written by Carlos Tello, PhD on August 17th, 2020
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The COMT gene encodes a protein that breaks down the neurotransmitters dopamine, epinephrine, and norepinephrine. Certain variants have been associated with schizophrenia. Read on to learn where your COMT gene stands!

What Is the COMT Gene?

The COMT gene codes for an enzyme called catechol-o-methyltransferase (also called COMT). As its name implies, COMT transfers a methyl group to catechol-containing compounds. COMT uses SAM-e as its methyl donor. Therefore, having either too little SAM-e, or too much S-adenosylhomocysteine (SAH) — which is formed when SAM-e loses its methyl group — results in inhibition of COMT [R, R].

The main function of COMT is to help break down catecholamines, a family of neurotransmitters that includes dopamine, norepinephrine (also known as noradrenaline), and epinephrine (also known as adrenaline) [R].

COMT is widely distributed in organs such as the brain, adrenal glands, liver, kidneys, lungs, intestines, and mammary glands [R, R].

The COMT gene encodes an enzyme of the nervous system that breaks down the neurotransmitters dopamine, norepinephrine, and adrenaline by transferring a methyl group to them, from SAM-e.

Dopamine Neurotransmission and Inactivation by COMT

Dopamine is a neurotransmitter involved in multiple cognitive and behavioral processes such as executive function, motivation, reward, and movement control. Outside the brain, it helps relax the blood vessels, increase urine output, reduce gastrointestinal motility and insulin production, and regulate immune cell activity [R, R].

Importantly, dopamine must be quickly inactivated to terminate the signal. Failing to do so is associated with schizophrenia and other mental problems. In most parts of the brain, this is achieved through dopamine transporters that promote its removal. In the prefrontal cortex, where dopamine transporters are much less abundant, dopamine breakdown by COMT accounts for over 60% of dopamine inactivation [R, R].

Dopamine is a neurotransmitter involved in multiple cognitive, behavioral, and physiological processes. COMT inactivates dopamine to terminate its transmission.

Dopamine and Schizophrenia

Schizophrenia is a serious mental disorder mainly characterized by ‘psychosis’ (break from reality), which typically consists of hallucinations and delusions. Other symptoms of schizophrenia include disorganized thinking and behavior, emotional blunting, and cognitive impairment. Excessive dopamine and reduced glutamate transmission are believed to contribute to the symptoms of this condition [R].

Altered dopamine transmission is associated with schizophrenia.

Your COMT Results for Schizophrenia

 

 

SNP Summary and Table

Primary SNP: COMT rs4680

  • ‘G’ = Increased risk of schizophrenia in White people
  • ‘A’ = Reduced risk of schizophrenia.
  • 41% of the world population has genotype ‘GG’
  • In people with European ancestry, both alleles are equally frequent

Other Important SNPs 

COMT rs737865

  • ‘A’ = Normal risk of schizophrenia
  • ‘G’ = Reduced risk of schizophrenia and milder symptoms 
  • 60% of the world population has genotype ‘AA’
  • The ‘G’ variant is slightly more common in European descendents

COMT rs4633

  • ‘C’ = Normal risk of schizophrenia
  • ‘T’ = Increased risk of schizophrenia but better response to treatment
  • The genotype distribution is very similar to that of rs4680 for all ethnicities

COMT rs2020917 

  • ‘C’ = Normal risk of schizophrenia
  • ‘T’ = Reduced risk of schizophrenia
  • The genotype distribution is very similar to that of rs737865 for all ethnicities

COMT rs165774 

  • ‘G’ = Increased risk of schizophrenia
  • ‘A’ = Reduced risk of schizophrenia
  • Only 5% of the world population has genotype ‘AA’
  • Allele ‘A’ is slightly more common in people of European ancestry (10% of ‘AA’)

COMT rs9332377 

  • ‘C’ = Normal risk of schizophrenia
  • ‘T’ = Increased risk of schizophrenia
  • Worldwide, 70% of the population has ‘CC’
  • The ‘T’ variant is even less common in people of European ancestry

 

SNP Table

 

 

Influence of COMT Variants on Schizophrenia

Rs4680

By far, rs4680 is the most widely-studied COMT gene variant. Its minor ‘A’ allele encodes a less-stable protein that results in reduced COMT levels and activity [R, R].

The major ‘G’ variant at this polymorphism has been associated with a slightly increased incidence of schizophrenia in White people but not in Asian people, as well as with worse response to treatment. In turn, the ‘A’ variant predicts more aggressive behavior in people with this condition and has been weakly associated with an earlier onset [R, R, R, R, R].

A widely-investigated COMT underactive variant is associated with increased rates of schizophrenia in White people.

Other Variants

The minor ‘G’ variant of rs737865 has been associated with a reduced risk of schizophrenia and severity of symptoms in South African and Brazilian populations. Studies failed to link this polymorphism to changes in COMT expression, protein levels, and enzyme activity [R, R, R, R].

The minor ‘T’ allele of rs4633 increases COMT expression. This variant is associated with an increased risk of schizophrenia but also better response to treatment [R, R, R, R, R, R].

The minor ‘T’ allele of rs2020917 increases COMT expression and, possibly, activity. This variant was associated with a reduced risk of schizophrenia in a South African study [R, R].

The minor ‘A’ allele of rs165774 increases COMT gene expression, but encodes a COMT protein with reduced activity. The major variant at this polymorphism has been associated with schizophrenia [R, R, R].

The minor ‘T’ variant of rs9332377 was associated with schizophrenia in an Indian study [R].

Finally, the minor ‘G’ variant of rs4818 encodes a protein with reduced activity. This variant has been associated with a reduced risk of treatment resistance in schizophrenic women [R, R].

Several COMT variants have been associated with changes in the incidence and severity of schizophrenia.

Recommendations

Lifestyle

Reducing Stress

People with underactive COMT variants (often called ‘worriers’) have excessive levels of norepinephrine and epinephrine in response to stress. This reduces their ability to adapt to stressful situations and worsens their cognitive performance in these conditions [R].

Chronic stress damages mental health and can cause different types of psychiatric conditions, including anxiety disorders, mood disorders, and schizophrenia. In two studies from Belgium and the Netherlands, carriers of the ‘A’ variant at rs4680 had an increased risk of developing psychosis from psychological stress [R, R].

Conversely, the incidence and severity of psychotic experiences from traumatic stress seems to be higher in carriers of the ‘G’ variant at this polymorphism [R, R, R]. 

We recommend addressing sources of stress in your life, either by taking up a stress-busting hobby (such as yoga or meditation) or seeking professional help.

Stress increases the risk of several psychiatric disorders. COMT activity influences stress susceptibility and risk of psychosis from stressful conditions.

Avoiding Recreational Drugs

Cannabis is one of the most commonly-used recreational drugs. Although its active compound THC can have some medical applications (especially in the treatment of spasms from multiple sclerosis, and neuropathic pain), high and repeated doses can cause psychosis, increased anxiety, delayed recall time, and impaired mental performance [R, R, R].

The major ‘G’ variant of rs4680 has been associated with increased risk, earlier onset, and worse symptoms of psychosis and schizophrenia from cannabis use. However, carriers of the ‘A’ variant are more prone to a lifetime use of cannabis [R, R, R, R, R, R, R].

Methamphetamine is a potent stimulant that is most often used as a recreational drug and, less commonly, as a treatment for ADHD and obesity. Its use is strongly linked to schizophrenia, with ~13% of abusers experiencing psychotic symptoms [R].

In an Iranian study, psychosis caused by methamphetamine dependence was associated with increased COMT expression. This suggests that people with active COMT variants may be more prone to methamphetamine-induced psychosis [R].

Cannabis and methamphetamine are two recreational drugs that may cause psychotic symptoms when repeatedly used. People with active COMT variants may be at increased risk of psychosis from their use.

Author photo
Carlos Tello
PhD

Carlos received his PhD and MS from the Universidad de Sevilla.

Carlos spent 8 years in the laboratory investigating mineral transport in plants. He then started working as a freelancer, mainly in science writing, editing, and consulting. Carlos is passionate about learning the mechanisms behind biological processes and communicating science to both academic and lay audiences. He strongly believes that scientific literacy is crucial to maintaining a healthy lifestyle and avoiding falling for scams.

Disclaimer

The information on this website has not been evaluated by the Food & Drug Administration or any other official medical body. This information is presented for educational purposes only, and may not be used to diagnose or treat any illness or disease.

Also keep in mind that the “Risk Score” presented in this post is based only on a select number of SNPs, and therefore only represents a small portion of your total risk as an individual. Furthermore, these analyses are based primarily on associational studies, which do not necessarily imply causation. Finally, many other (non-genetic) factors can also play a significant role in the development of a disease or health condition — therefore, carrying any of the risk-associated genotypes discussed in this post does not necessarily mean you are at increased risk of developing a major health condition.

Always consult your doctor before acting on any information or recommendations discussed in this post — especially if you are pregnant, nursing, taking medication, or have been officially diagnosed with a medical condition.

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