Can This Gene Influence Your Risk of Anxiety Disorders (COMT)?

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.

Catechol Neurotransmitters and Inactivation by COMT

Dopamine is a neurotransmitter involved in multiple cognitive and behavioral processes such as executive function, motivation, reward, and movement control [R].

Importantly, dopamine must be quickly inactivated to terminate the signal. Failing to do so is associated with many mental disorders such as schizophrenia and addictive behaviors. 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].

Norepinephrine and epinephrine are two neurotransmitters and stress hormones released by the adrenal glands during the ‘fight-or-flight’ response. They prepare the brain for stressful situations by promoting arousal, alertness, fear, and memory. Additionally, they increase heart and breathing rate, blood and sugar supply to the muscles, and blood pressure [R, R].

Although these neurotransmitters are vital for normal physiology, the sustained stimulation of their receptors increases pain and anxiety; therefore, it’s essential to block their transmission when no longer needed. COMT plays a key role in their inactivation, especially of epinephrine. Norepinephrine is preferentially inactivated by removal, but COMT breakdown is the preferred mechanism in kidney arteries and the liver [R, R, R].

Dopamine is a neurotransmitter involved in multiple cognitive, behavioral, and physiological processes, while both epinephrine and norepinephrine prepare the body for stressful situations. Their breakdown by COMT prevents several psychiatric disorders.

Catecholamines and Anxiety Disorders

COMT’s role in the stress response has earned it the nickname the “warrior / worrier” gene [R]:

• “Warriors” are people with highly active COMT variants. Because epinephrine and norepinephrine are released during stress, having increased COMT activity allows them to break these neurotransmitters down more quickly, which helps them recover during periods of stress.
• By contrast, “worriers” carry underactive variants that break down these neurotransmitters more slowly, meaning that it generally takes them longer to adapt to stress.

As will be discussed below, underactive COMT variants are associated with some anxiety disorders due to imbalances in catecholamine neurotransmission. These include [R]:

• Obsessive-Compulsive Disorder (OCD): a disorder with recurring, unwanted thoughts (obsessions) and the urge to do certain routines repeatedly (compulsions). People with OCD have increased dopamine and glutamate activity but reduced GABA and serotonin levels [R, R, R].
• Post-Traumatic Stress Disorder (PTSD): a disorder with flashbacks, nightmares, and severe anxiety caused by a traumatic event. People with PTSD have excessive levels of epinephrine, norepinephrine, and glutamate [R, R].
• Social phobia: a disorder with fear and anxiety in social situations. Imbalances in dopamine and serotonin activity seem to cause this condition [R].
• Anorexia: an eating disorder linked to anxiety with severe food restriction and desire to lose weight. People with this disorder have alterations in serotonin and dopamine activity.

People with underactive COMT variants have high epinephrine and norepinephrine levels. This makes them worse at coping with stress. Imbalances in catecholamine neurotransmission put them at increased risk of some anxiety disorders.

SNP Summary and Table

Primary SNP: COMT rs4680

• ‘G’ = Normal risk of anxiety disorders
• ‘A’ = Increased risk of anxiety disorders
• 41% of the world population has genotype ‘GG’
• In people with European ancestry, both alleles are equally frequent

Other Important SNPs 

COMT rs4633

• ‘C’ = Normal risk of anxiety disorders
• ‘T’ = Increased risk of anorexia
• The genotype distribution is very similar to that of rs4680 for all ethnicities

COMT rs2075507

• ‘A’ = Increased frequency of compulsive behaviors in people with OCD
• ‘G’ = Normal frequency of compulsive behaviors in people with OCD
• Only 12% of the world population has genotype ‘GG’
• The ‘G’ variant is slightly more common among European descendants

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].

In agreement with its association with the anxious ‘worrier’ phenotype, the following anxiety disorders were more common among carriers of ‘A’ variant at this polymorphism:

• OCD (especially in men) [R, R, R, R]
• PTSD [R, R]
• Social phobia (in autistic children) [R]

A widely-investigated COMT underactive variant is associated with increased rates of anxiety disorders such as OCD, PTSD, and social phobia.

Other Variants

The minor ‘T’ allele of rs4633 increases COMT expression but has been associated with conditions typically linked to underactive variants (such as cancer and pain sensitivity), so it might reduce COMT activity. The ‘TT’ genotype was associated with anorexia in a Chinese population [R, R, R].

In people diagnosed with OCD, the major ‘A’ allele of rs2075507 was associated with compulsive behaviors such as excessive washing and orderliness. This polymorphism was unrelated to COMT activity in a study on human brain samples [R, R].

Two COMT variants have been associated with anorexia and compulsive behaviors.