The combination of COMT and MAO-A variants can affect mood regulation and neurotransmitter balance. Add in a DRD2 variant and you have very different phenotypes.
Definition of phenotype: the expression (set of symptoms) of your genes as influenced by your epigenetic factors such as your diet, lifestyle and environment. You can change your phenotype by changing your epigenetics as this will in turn change the expression of your genes.
Here is a quick breakdown of these different phenotypes. I have also included a fictional character for each one to help you see how this could play out, especially with regards to risks, predispositions , mental and physical symptoms that might present. Keep in mind, though, that the effects of these enzyme activities are also influenced by other genetic factors and environmental stressors. Personal history, stress, diet, sleep, and overall health can influence how these enzymes impact mood and behavior. So while someone with a specific genotype could tend to lean towards a certain phenotype, it would ultimately depend on a combination of their genetic make-up, and other internal and external epigenetic factors.
When I am doing a feedback report for a genetic test, I take a look at this in connection with the client. This can be of benefit when it comes to making recommendations in how they can adjust their diet, certain lifestyle choices and habits and clean these up to help their genes express better. This also will determine what supplements will and won’t work for them. Sometimes we are not even aware of how the small choices we make each day impact our physical and mental health.
Slow COMT / Fast MAO-A / DRD2 (Wired but tired phenotype)
- With this phenotype, you’re likely to experience higher dopamine levels especially in the prefrontal cortex due to slow COMT. You will likely be quite good at problem solving and have better attention and focus and memory (slow COMT) but on the other hand you will probably struggle with mood stability due to low serotonin (Fast MAO-A) The Reward factor is low, and there may be an increased risk of addictive behaviors and mood swings due to DRD2.
Fast COMT / Slow MAO-A / DRD2: ( )
- You may struggle with cognitive issues like poor focus, attention and lack of motivation due to rapid dopamine depletion (fast COMT) but may find that you have greater emotional stability thanks to higher serotonin (slow MAO-A) which means you are able to cope better when under stressful situations. The Reward factor remains low, and the addiction tendency remains the same due to the DRD2.
Let’s break it down a bit further.
COMT -fast or slow
The slow COMT variant (Met/Met, AA) leads to a slower breakdown of the neurotransmitters dopamine, norepinephrine and epinephrine. This can lead to higher levels in the brain, particularly the prefrontal cortex and basal ganglia, that stick around for longer than what they should. When this happens it can lead to increased anxiety, mood swings and irritability.
The fast COMT variant (val/val, GG) leads to an accelerated breakdown of the neurotransmitters dopamine, norepinephrine and epinephrine, which can lead to lower levels in the brain. This affects executive functioning like working memory, focus and attention. (also seen in inattentive ADHD)
MAO-A- fast or slow
A fast MAO-A variant leads to an accelerated breakdown of the neurotransmitters serotonin, metatonin, dopamine,epinephrine and norepinephrine in the brain. Which results in lower levels of these affecting mood, and potentially leading to anxiety, and reduced motivation and impacting sleep.
A slow MAO-A variants leads to a reduced breakdown of the neurotransmitters serotonin, dopamine, and norepinephrine in the brain. Which results in higher serotonin availability. This can provide a buffer against emotional volatility and protect against anxiety or depression.
DRD2
DRD2 is a dopamine receptor located in the stratum, hippocampus, amygdala and cerebral cortex. The DRD2 gene codes the dopamine receptor DRD2. The variant causes a reduced number of dopamine binding sites in the brain, resulting in reduced dopamine signaling which means that individuals with mutations are less sensitive to the activation of dopamine- based reward system and this makes them more likely to be predisposed to addictive behaviour.
A simple example would be while some people may feel satisfied after one block of chocolate, it may require a whole slab for someone with a variant in DRD2 to feel the same sense of satisfaction which is why they often are led to overeating. They need stronger stimuli to experience the same level of reward as individuals with a normal receptor density, which is what often leads to addictive behaviors or seeking out more intense experiences. Shopping, gaming, spending money, seeking out new experiences, trying new hobbies, or over eating are often part of the reward seeking.
The DRD2 receptors play an important role in addiction and eating behaviour as they are involved in the dopamine based reward circuitry. This receptor has been associated with Parkinson’s Disease, alcohol addiction, opioid addiction, ADHD with hyperactivity and impulsivity, and binge-eating, affecting working memory.
Slow COMT / Fast MAO-A / DRD2 (Wired but tired phenotype)
Greg (fictional character) has this combination. He works really hard and loves his job. In fact, he finds it hard to stop working! Greg is quite meticulous when it comes to detail and work ethic, paying close attention to small details. He can sit for long periods of time, focusing on his work without any problems. He likes things to be “just right”, perhaps even bordering on some perfectionist tendencies. However, when things don’t go his way, he finds himself reacting with annoyance and anger. Small things often annoy him, like spelling and grammatical errors.
Greg finds it hard to switch off and relax. He feels the constant need to keep going. Others would describe him as a workaholic. When he isn’t working, he likes to participate in sports, go to the gym or do fun and exciting activities on the weekend like go-cart racing and mountain biking.
He gets worked up quite quickly and is prone to a quick temper. Everybody knows to be careful around him, because he is a “ticking time bomb”. He finds it hard to calm down after he has exploded and often turns to alcohol to try and calm his nerves, often making the situation worse.
He likes coffee and drinks a lot, but finds that he often feels especially anxious, jittery and “wired” after doing so and struggles with motivation and fatigue. He finds himself over thinking things and often over reacting. This is Greg at his worst.
What Greg doesn’t know is that he struggles with mood regulation and poor stress response not only due to his genetic variants, but also due to his lifestyle.
Greg has many admirable traits which he can use to his advantage. His ability to work hard and focus makes him good at his job. He is also fun to be around. When he is on holiday, others find him easier to be around, noticing how he tends to be less explosive and volatile when relaxed and not hyper focused on work.
Greg tends to react badly to stimulants, although he may not always recognize this. Drinking red bull makes him feel amazing, but later on in the day he crashes and his anxiety spikes. Greg also struggles with pain, and tends to have a lot of tension in his neck and shoulders. He has trouble falling asleep and wakes up often in the night. He constantly feels tired and craves caffeine. He also struggles with digestive issues from time to time.
Greg’s slow COMT is causing higher levels of neurotransmitters which is aiding his cognitive ability to put his head down and work really well. But he does find that he struggles to feel any real sense of reward or satisfaction from his job due to his DRD2 variant. He may have a lot of dopamine floating around, but few and far between dopamine receptors for it to bind to, thus reducing the signaling of dopamine. Slow COMT also means he has more norepinephrine around and thus he has a higher stress response which is what is making him overreact, prone to anger and irritability. With his fast MAO-A, he is also prone to lower serotonin levels due to the enzyme breaking it down too quickly, giving rise to feelings of anxiety and overwhelm and making it hard to relax.
Fast COMT, Slow MAO-A and DRD2 (ADHD phenotype)
Susan (fictional character) finds it hard to focus for long periods of time. She is easily distracted and often finds her mind wandering. She gets bored easily and so finds it hard to stick to one interest or one hobby. She likes to try different things. She has had many jobs, mostly because when something doesn’t ignite her or interest her, she struggles with the motivation to do her job and so moves onto the next one. When she finds something she likes, she gives it 100%, often excelling in it. She is exceptionally good when deadlines are involved as this spurs her reward-based motivation.
Susan likes to explore her creativity, often in a childlike manner. She is laid back and easy going, tending to handle stressful situations well. But when a stressful situation that is long and drawn out, she finds she can buckle under the extended strain of stress. At times like this, Susan finds herself becoming extremely anxious and often depressed and will turn to alcohol. She also withdraws from friends and family and can become paranoid, sometimes thinking people are out to get her. She will tend to overthink and worries a lot when she is anxious and stressed, and will rely heavily on caffeine to get through the day.
Susan often wonders why she struggles to feel excitement and intense joy like other people around her. She describes it as “feeling flat”. When she completes a task, she feels a sense of relief, more than a sense of accomplishment. She often feels detached, and apathetic at times, and can find if hard to feel enthusiastic about something.
She tends to suffer with headaches and allergies, often complaining of gut issues like bloating. She also struggles with constipation. She has restless legs at night and is a light sleeper.
Susan’s fast COMT is leading to lower levels of dopamine and norepinephrine. Since Susan has ADHD, she struggles with inattentiveness and executive function such as working memory and focus. She tends to cope well under stress and has good emotional stability. However, she struggles with low mood around the time of her menstrual cycle each month. Perimenopause is hitting Susan hard, causing an imbalance in her neurochemicals and hormones which is leading to anxiety and depression. This is due to her fast COMT, because it is breaking down estrogen too quickly, leading to lower estrogen as well as dopamine, thereby affecting her mood. However, Susan mostly has good emotional stability thanks to her slow MAO-A which keeps her levels of serotonin at a good level. She can, however go through periods of anxiety and depression, especially when undergoing continuous stress. This can be due to neurotransmitters becoming imbalanced when under stress, causing a spike in glutamate, depleting GABA and with fast COMT and DRD2, causing dopamine to be low resulting in decreased motivation and depression. Too much serotonin and glutamate can cause anxiety.
Slow COMT, slow MAO-A and DRD2: (HSP phenotype)
Judy (fictional character) struggles with anxiety. She is very easily over stimulated and is sensitive to stimuli of any kind. She has been told that she is “too sensitive”. Her emotions and responses are big. Judy struggles with both food and environmental allergies as well as histamine intolerance. She reacts quickly to chemicals and finds herself getting hives when exposed to perfume or products with fragrances. She often has headaches, itchy skin, and watery eyes.
Judy wonders why she is so reactive to seemingly everything in her environment. She tends to isolate because she hates making a fuss and being told she is sensitive or too emotional.
Her highly sensitive nature (HSP), both emotionally, mentally and psychically makes her feel the world is too much for her but on the other hand she is told that she is a great listener and friend, often going out of her way for others and highly empathetic.
In summary, Judy’s slow COMT and slow MAO-A is causing significantly elevated levels of neurotransmitters. This results in mood instability, anxiety, and challenges with emotional regulation. She has heightened sensitivity to stressors and potential side effects from methylated supplements, impacting her ability to maintain stable mental and emotional health. Due to her DRD2, she can struggle with shyness, worry as well as attention.
Q: What about intermediate variants in COMT and MAO-A?
Interesting question. If your COMT is intermediate but you have either a slow or fast MAO-A, it can tend to act like a slow COMT at times when your epigenetic factors are contributing or when methylation is not supported.
Q: How would Greg, Susan and Judy in these instances help their phenotype express better?
It would require some work on their part to change various epigenetic factors that are contributing towards negative genetic expression. A careful consideration of their diet, various lifestyle factors such as sleep hygiene, stress management, lifestyle habits such as smoking, drinking alcohol, exercise, of course other variants in key biological pathways that could be playing a part, and any environmental factors that could be contributing: exposure to heavy metals, toxins and the like.
When I provide feedback for a genetic test, or in my coaching, these modifiable areas are given attention and guidance is provided on how to change,implement or tweak all these avenues.
If you are interested in genetic testing,or if you currently have a genetic test and would like some guidance on it please feel free to contact me via the contact page on my website.
References for Fast COMT, slow MAO-A and DRD2:
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Simpson EH, Morud J, Winiger V, Biezonski D, Zhu JP, Bach ME, Malleret G, Polan HJ, Ng-Evans S, Phillips PE, Kellendonk C, Kandel ER. Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum. Learn Mem. 2014 Mar 17;21(4):205-14. doi: 10.1101/lm.032094.113. PMID: 24639487; PMCID: PMC3966542.
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Serý O, Drtílková I, Theiner P, Pitelová R, Staif R, Znojil V, Lochman J, Didden W. Polymorphism of DRD2 gene and ADHD. Neuro Endocrinol Lett. 2006 Feb-Apr;27(1-2):236-40. PMID: 16648784.
- Dopamine Genes and ADHD: a review; Salvatore DiMaio; Nathalie Grizenko, MD; Ridha Joober, MD, PhD
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Stein DJ, Newman TK, Savitz J, Ramesar R. Warriors versus worriers: the role of COMT gene variants. CNS Spectr. 2006 Oct;11(10):745-8. doi: 10.1017/s1092852900014863. PMID: 17008817.
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Chen H, Pine DS, Ernst M, Gorodetsky E, Kasen S, Gordon K, Goldman D, Cohen P. The MAOA gene predicts happiness in women. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jan 10;40:122-5. doi: 10.1016/j.pnpbp.2012.07.018. Epub 2012 Aug 4. PMID: 22885141; PMCID: PMC6299830.