What Does The COMT Gene Do?
One of the most important single genes when it comes to cognitive function and mental performance is the COMT gene.
The COMT gene encodes for the catechol-O-methyltransferase (COMT) enzyme. This enzyme is critical for brain function, as it is responsible for degrading catecholamines.
Catecholamines are the class of neurotransmitters that include dopamine, epinephrine, norepinephrine. These transmitters are crucial for maintaining proper mental function.
However, you do not want too many of these transmitters to build up in the synapses. So, the COMT enzyme is responsible for breaking down and clearing these neurotransmitters to free up space for future transmission.
So, through encoding the COMT enzyme, COMT genes influence the level of dopamine and norepinephrine. This can have a wide-ranging effect on cognitive performance, mood, memory, and other aspects of mental health.
COMT is the most investigated gene when it comes to catecholamines. If you have an interest in nootropics or cognitive enhancement, you may find it valuable to understand how it works.1Chen J, et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain, Am J Hum Genet. 2004
Sex can play a difference in COMT expression. Levels can vary between men and women. For men, COMT activity in prefrontal cortex is 17% higher than that in women.2Chen J, et al.Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain,<Am J Hum Genet. 2004
What is COMT polymorphism?
There are variations in the COMT gene that can change how it functions. Single nucleotide polymorphism (SNP) refers to adjustments in genes that causes it to express different traits.
For COMT there are several SNPs that researchers have studied, including COMT rs4680, COMT rs4633, COMT rs5993883, and COMT rs737865. Each of these variants could mean significantly different effects on mental processes.3Weili Jiang,et al. Genetic influences on insight problem solving: the role of catechol-O-methyltransferase (COMT) gene polymorphisms Front. Psychol. 2015
For example, previous studies found that rs737865, rs4680, and rs5993883 SNPs of COMT genes were strongly correlated with divergent thinking.4Shun Zhang.An Exploratory Study on DRD2 and Creative Potential,< Creativity Research Journal, 2014
According to current research, creativity involves two components: divergent thinking and convergent thinking. So, people with these variants of COMT may have increased natural abilities with creative problem-solving.5Guilford, J. P. Creativity American Psychologist. 1950
In a similar manner, rs4633, rs4680, and rs5993883 variants of COMT genes correlated with what’s known as insight problem-solving.6Weili Jiang, et al. Genetic influences on insight problem solving: the role of catechol-O-methyltransferase (COMT) gene polymorphisms Front. Psychol. 2015
Warrior vs Worrier
In particular, COMT rs4680 (aka (Val158Met), the most commonly studied COMT gene polymorphism. It seems to be correlated with learning, insight, problem solving, working memory and divergent thinking.
If you have this particular SNP, you express either Val (G) dominant or Met (A) dominant subtypes. These subtypes correspond to either “warrior” or “worrier” subtypes.7Stein DJ, et al. Warriors versus worriers: the role of COMT gene variantsCNS Spectr. 2006
COMT rs4680 (G) – Val158 allele is considered the “Warrior” type.
People with this gene variant have higher activity of COMT enzyme, resulting in lower levels of Dopamine and Norepinephrine.
It may have an advantage in processing negative stimuli. This means that under conditions of increased dopamine release (e.g., stress), individuals with Val158 alleles may have improved dopaminergic transmission and better performance,
There is a slight increase in risk for schizophrenia with this gene.8Michael F. Egan, et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia Proc Natl Acad Sci U S A. 2001
On the other hand, COMT rs4680 (A)- Met158 is the “worrier.”
These people have lower COMT enzyme activity, resulting in higher levels of dopamine and norepinephrine. This subtype may have improved processing efficacy in the prefrontal cortex, possibly due to higher dopamine levels.9Heinz A, Smolka MN. The effects of catechol O-methyltransferase genotype on brain activation elicited by affective stimuli and cognitive tasks Rev Neurosci. 2006
Carriers of Met158 allele may be more reactive to unpleasant stimuli, leading to more anxiety, hence the “Worrier” name. They are also associated with improved working memory, executive functioning, and attention control,
This variant is also associated with the process of Insight Problem Solving. This refers to “A-ha!” moments, and is a more direct route of creativity in the brain vs the analytical (time-consuming) route to problem-solving.10Weili Jiang, et al Genetic influences on insight problem solving: the role of catechol-O-methyltransferase (COMT) gene polymorphisms Front. Psychol. 2015
Does everyone have the COMT gene?
Everyone has some variation of the COMT gene, as dopamine must be broken down or you will die. The question is to what degree and what variation do you have of the COMT gene.11He Q, et al.COMT Val158Met polymorphism interacts with stressful life events and parental warmth to influence decision making Sci Rep. 2012
Relationship To Dopamine
The relationship between dopamine levels and brain function is complicated. Poor performance on cognitive tasks by both deficient and excessive amounts of DA is best illustrated as an inverted U-shaped dose-response curve.
In other words, more dopamine is good to a point and then too much begins to have a negative effect.12Vijayraghavan S, et al Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory Nat Neurosci. 2007
When faced with stressful life events, carriers of the “Worrier” Met allele (the most common variant of the COMT gene) had a higher risk of poor decision making. This is a hallmark of depression, schizophrenia, and addiction disorders.13He Q, et al. COMT Val158Met polymorphism interacts with stressful life events and parental warmth to influence decision makingSci Rep. 2012
Worriers tend to have higher dopamine levels in the prefrontal cortex (PFC), which is linked to several psychiatric disorders
One study compared 27 major depressive disorder patients to 42 healthy subjects with varying degrees of the COMT genotype. It revealed a statistically significant interaction between depression and COMT genotype activity in the hippocampus using MRI.
Researchers concluded that the Val158Met COMT polymorphism may influence depression.14Otsuka Y, et al. COMT polymorphism regulates the hippocampal subfield volumes in first-episode, drug-naive patients with major depressive disorder Neuropsychiatr Dis Treat. 2019
There is some evidence that suggests that “Worrier” Met alleles are associated with higher levels of anxiety.15Stein DJ, et al. Warriors vs Worriers: the role of COMT gene variants, CNS Spectr. 2006
Learning and Memory
Studies have found that carriers of the “Worrier” Val have the best performance on executive functions, like working memory and cognitive flexibility, which play an important role in insight problem-solving.16Egan MF, et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia Proc Natl Acad Sci U S A. 2001
A meta-analysis of a specific executive function task, the Wisconsin Card Sorting Test, found that individuals with this genotype performed better in the Wisconsin Card Sorting Test than those with the “Warrior” genotype.17Barnett JH, et al. Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls Mol Psychiatry. 2007
Evidence shows that dopamine may affect insight problem solving through its effects on individuals’ working memory and cognitive flexibility.18K.J. Gilhooly, etal. Executive functions in insight versus non-insight problem solving: An individual differences approach Thinking & Reasoning. 2009
In a similar vein, norepinephrine may significantly impact cognitive flexibility, and therefore improve solving insight. problems.19Alexander JK, et al. EBeta-adrenergic modulation of cognitive flexibility during stress J Cogn Neurosci. 2007
COMT metabolizes all catecholamines, including dopamine and norepinephrine, which is most likely why it has this effect on these cognitive processes.
It would make sense, then, that the variant that does not metabolize as much of these neurotransmitters would improve these processes.
COMT and ADHD
Val158 carriers (“Warriors”) tend to have prefrontal hyperactivation and worse performance on memory and attention.flexibility, and therefore improve solving insight. problems.Evidence shows that dopamine may affect insight problem solving through its effects on individuals’ working memory and cognitive flexibility.20Michael F. Egan, et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia Proc Natl Acad Sci U S A. 2001
Conversely, Met158 (“Worriers”) substitutions are associated with an advantage in memory and attention tasks.21Heinz A, Smolka MN. The effects of catechol O-methyltransferase genotype on brain activation elicited by affective stimuli and cognitive tasks Rev Neurosci. 2006
There is a possible link between COMT rs4680A and PD. Currently, the data is conflicting, and more study is needed, but there is some preliminary evidence.22Białecka M, et al. Association of COMT, MTHFR, and SLC19A1(RFC-1) polymorphisms with homocysteine blood levels and cognitive impairment in Parkinson’s disease Pharmacogenet Genomics. 2012