The Genetics of Anxiety & The Role of COMT:
Generalized Anxiety and Panic Disorder are two of the most common psychiatric diagnoses in the United States today, both of which can negatively interfere with the patient’s quality of life and activities of daily living. Unfortunately, even with the high rates of diagnosis, evidence suggests that many cases are missed, making anxiety related symptoms even more widespread in our society that previously thought. Mainstream treatment is generally a combination of psychotherapy and medication, but even still many patients still suffer from debilitating symptoms (1). Finding the cause is the goal, but are the onset of these symptoms related more to nature? Or nurture? Likely, it’s a combination of both.
Family and twin studies have shown that genetic factors have a significant contribution when it comes to the pathogenesis of anxiety disorders. Specifically, some studies have reported a four- to six-fold increase in odds of also being diagnosed with an anxiety related disorder if a first-degree relative has been diagnosed with panic disorder, social phobia, or generalized anxiety. The genetics are complicated, with familial inheritance being attributed to a combination of abnormalities in a multitude of genes. In addition, environmental influences also play a major role, making it hard to tease out the cause of these symptoms, complicating treatment. (2).
When it comes to the genetics of anxiety however, one gene stands out in the literature – and it is the gene that codes for the enzyme catechol-O-methyltransferase.
Catechol-O-methyltransferase, commonly referred to as COMT, is an enzyme that inactivates catecholamine neurotransmitters. This includes dopamine, epinephrine, and norepinephrine. In humans, this enzyme is coded for by a gene on chromosome 22 and is able to transcribe two isoforms of the enzyme: soluble cytoplasmic COMT and membrane-bound COMT. In regards to metabolizing catecholamines, membrane-bound COMT is much more effective than cytoplasmic, making it the relevant isoform for the study of its relationship to psychiatric presentations (3).
To understand the role of COMT, it is important to understand the role of catecholamines. Epinephrine and norepinephrine are released by the adrenal gland in times of stress – think ‘fight or flight’. So, when an individual is under stress, whether acute or chronic, the body pumps out these chemicals to get you fleeing. Then, multiple enzymes work to break down these catecholamines and return the body to baseline; one of these enzymes being COMT.
Dopamine, another catecholamine also broken down my COMT, however plays a wider role. It is integral to how humans feel pleasure, and contributes to the ability to think and plan. Therefore, links have been made between conditions such as ADHD, schizophrenia, and drug addiction when dopamine levels are off.
COMT enzyme activity in human physiology can vary depending on a polymorphism that, if present, can reduce the affinity this enzyme has for the various catecholamines, slowing their breakdown. The specific polymorphism discussed in research that contributes to the efficacy of this enzyme involves a single amino acid switch from valine (val) to methionine (met) at codon 158 on membrane-bound COMT. Those who are homozygous for valine have the highest efficiency and binding capability to catecholamines, heterozygotes (val/met) have intermediate efficiency, and homozygous methionine individuals have the lowest COMT activity (3).
“Finding the cause is the goal, but are the onset of these symptoms related more to nature? Or nurture? Likely, it’s a combination of both.”
Both animal and human studies have been done to look at the effects of varying COMT efficacy and resulting psychiatric symptoms. A study in 2008 done on mice, bred to overexpress the valine-COMT genotype, gave basic insight into the expressed phenotype of these mice versus those with the val/met or met/met polymorphisms. They found that a deficiency of COMT (reduced function seen in val/met or met/met genotypes) resulted in higher anxiety responses, including heightened startle activity, greater pain perception, exaggerated stress-induced hyperthermia, and a blunted stress response. On the other hand, a deficiency of COMT improved working memory. This indicated a possible evolutionary trade off between cognitive and behavioral/affective functions when comparing the various polymorphisms of COMT (4).
Though human studies are a bit trickier to draw conclusions from, as the polymorphisms have a high level of complexity and the actual clinical presentation of anxiety can vary widely between individuals, this evolutionary trade off is being found in humans as well (4). This is likely what leads to mixed conclusions, as some reports vary on which polymorphism has the highest rate of anxiety. As for the evolutionary trade off, a meta-analysis performed in 2015 found that those with homozygous methionine polymorphisms were less efficient than valine homozygous individuals when engaging in tasks requiring emotional processing, but more efficient when those tasks were primarily utilizing cognitive activity. Therefore, genetic testing may give insight into what is triggering the anxiety and potential ideas on how to manage it more effectively (3).
One management technique that seems to have varying levels of success based on whether the val158met polymorphism is present or not is in cognitive behavioral therapy (CBT). Early studies have found that those with the met/met genotype, or those considered to have the cognitive advantage, may benefit less from exposure-based cognitive behavioral therapy than those carrying at least one valine-allele (5). This was further supported in 2015, when researchers looked at the polymorphism in regards to cognitive-behavioral therapy outcomes in cocaine-dependent individuals. They too found that those who carried the valine allele appeared to respond better to CBT therapy (6). This may explain the great success some individuals have with CBT, but not others.
Obviously, this is a very complicated topic, but more and more people are having their genome tested (ie. 23andMe, Ancestry, etc). The understanding of these genetic polymorphisms and what that means for the individual may become more clear, hopefully providing insight into the cause and most effective, personalized treatment from those suffering from a condition. In psychiatry, COMT is proving to be one of those insightful genes.
LyfeCheck offers comprehensive genetic testing, including COMT evaluation. For more information visit www.ayumetrix.com or email info@ayumetrix.com.
– Mary Hall, ND, LAc
Sources:
1. https://pubmed.ncbi.nlm.nih.gov/25955736/
2. https://onlinelibrary.wiley.com/doi/full/10.1111/gbb.12423
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991696/
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2561993/
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004861/
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516567/
