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  • Writer's pictureDr Edin Hamzić

🧬 The COMT Gene Mutations

  • As you can assume from the post's title, this one is on the COMT gene and its corresponding mutations.

  • My aim with this blog post is to provide a short intro about the most popular genetic variants in the COMT gene and how to interpret different genotypes one can have for those COMT genetic variants and those are actually ones you can also find in the 23andMe raw genotype data.

  • So, let's jump right away.

What Is the COMT Gene?

  • Let's start by shortly explaining what is the role of the COMT gene.

  • ⚠️ The COMT gene encodes for the enzyme called catechol-O-methyltransferase.

  • The COMT enzyme, Catechol-O-methyltransferase, is crucial in the metabolic pathway of catecholamines.

  • What are catecholamines? Catecholamines are neurotransmitters such as dopamine, epinephrine, and norepinephrine and these are linked to multiple different traits among other many behaviorual traits (for example: mood, cognition, pain processing, and stress response), for more about this please continue reading.

  • FYI, In this blog post, when I refer to COMT, I refer to the catechol-O-methyltransferase, the enzyme that is encoded by the COMT gene, and if I refer to the gene, I will explicitly write the COMT gene.

⚠️ Why Is the COMT Gene Important?

  • ⚠️COMT plays a vital role in the degradation of the above-mentioned catecholamines (dopamine, epinephrine, and norepinephrine), particularly in the brain. In this way, COMT (the enzyme encoded by the COMT gene) helps maintain appropriate dopamine levels, influencing neurological functions such as mood, cognition, pain processing, and stress response.

  • Genetic mutations in the COMT gene can affect the activity level of the enzyme, thereby impacting the metabolism of catecholamines and potentially influencing individual differences in behavior, personality, and susceptibility to psychiatric disorders.

  • So, by checking genetic variants/mutations in the COMT gene we might get some insights that might explain some of our our personality traits.

  • ⚠️ If you already did a test like 23andMe, you can immediately check it by extracting genotype information from your 23andMe raw genotype data.

🤩 What Are the Best-Known COMT Gene Genetic Variants?

  • There are many genetic variants within the COMT gene, but only a handful have been associated with certain conditions and traits.

  • Among those, I will focus on those that can be found in the 23andMe raw genotype data, and those are:

    • rs4680: Also knonw as Worrier or Warrior SNP

    • rs4633: Risk for higher BMI and non-HDL cholesterol levels

  • rs165599: Related to anxiety-related personality traits, ADHD, schizophrenia

  • In the rest of the blog post , I will go into more detail about each of these SNPs (genetic variants/mutations), including how to extract those and inform the results.

rs4680: Warrior vs Worrier

  • The rs4680 is probably the most searched and looked for genetic variant in the COMT gene as it has been almost like "popularized" as the Warrior vs. Worrier genetic variant.

  • Actually, the COMT gene (in which rs4680 is located) became popular due to this genetic variant even though variants in the COMT gene have been associated with other traits, as I will show in the case of rs165599 and rs4633.

  • Specifically, the rs4680 genetic variants is a common coding single-nucleotide polymorphism (SNP), and it involves the substitution of guanine (G) with adenosine (A) in the exon three of the gene that leads to a change in the amino acid located at position 158 of the codon, but for those not familiar with genetics this does not mean much. In essence, this means that the rs4680 genetic variant has two alleles:

    • allele A and

    • allele G

  • Every person has a genotype created based on these two alleles inherited from their biological mother and biological father.

  • ⚠️ Following this, an individual can have the following genotypes for rs4680:

    • Genotype A/A: both alleles are A, from the father and mother.

    • Genotype A/G or G/A (the same just reversed): one allele is A, and the other is G, either from the mother or father.

    • Genotype G/G: both alleles are G, both from father and mother.

  • ⚠️ These genotypes (A/A, A/G and G/G) are ALSO often denoted following the amino acids being encoded depending on three different genotypes and you will find the following version for your rs4680 genotype like:

    • Genotype A/A can also be denoted as Val/Val since the A allele leads to the Valine amino acid to be encoded by the COMT gene.

    • Genotype Met/Val or Val/Met it is the same thing and it corresponds to A/G or G/A as Val stands for A allele as explained and G stand for Met which is the case when mutations happens. Mutation would be change from A to G.

    • Genotype Met/Met, finally as you would assume, this corresponds to G/G genotype.

What are the effects of rs4680 alleles?

  • More detailed explanation would be the following one:

    • The allele A (Worrier Allele) in the rs4680 SNP is associated with lower COMT enzymatic activity, which means that dopamine is not degraded by COMT enzyme and dopamine levels are higher. This is associated with:

      • Lower pain threshold

      • Enhanced vulnerability to stress, but also

      • Being more efficient at processing information under most conditions

    • The allele G (Warrior Allele) in the rs4680 SNP is associated with higher COMT enzymatic activity, which means that dopamine is efficiently degraded by COMT enzyme and dopamine levels are lower. This is associated with:

      • Higher pain threshold

      • Better stress resiliency, albeit with a

      • Modest reduction in executive cognition performance under most conditions

What does it mean to have different rs4680 genotypes G/G (Met/Met), G/A (Met/Val), A/A (Val/Val)

  • This change in amino acids from Valine (Val) to Methionine (Met) leads to creation of the COMT enzyme molecules that have different capability of breaking down dopamine.

  • For example, if an individual has the Val/Val (A/A) version of the COMT enzyme, it breaks down dopamine 40% faster than individual with the Met/Met genotype (G/G) [citation: (Chen et al., 2004; Lotta et al., 1995)]. This further means that , dopamine is available at the synapses for extremely short periods in the case of Val/Val carriers, whereas it is preserved intact for a longer period in the case of Met/Met carriers [citation- (Berryhill et al., 2013)]. This difference in how long dopamine is available in synapses influences neuronal activity with both shortness and overplus of dopamine producing different results.

  • Also, it has been suggested that an optimal dopamine availability seems to be maintained by the enzyme resulting from the heterozygous genotype Val/Met (Htun et al., 2014; Schacht, 2016).

  • In short, according to the study (you can check the original study here), the effect of three different rs4680 genotypes can be summarized like this:

    • If you have the AA genotype (Val/Val), you would be assigned to the so-called Worriers group with an advantage in memory and attention tasks.

    • If you have the GG genotype (Met/Val), you could be assigned to the so-called Warriors associated with multiple traits. More details about that in the next paragraph.

    • If you have the AG genotype (Met/Val), you will have an intermediate dopamine level and be somewhere between the two groups mentioned above.

rs165599 & Anxiety-related personality traits, ADHD & schizophrenia

  • The other important genetic variant/mutation in the COMT gene is rs165599.

  • The SNP rs165599 has been associated with anxiety-related personality traits, ADHD & schizophrenia.

  • Concretely, the genotype G/G genotype of rs165599 has been associated with increased risk susceptibility to schizophrenia.

rs4633 and Body Mass Index (BMI)

  • The third genetic variant in the COMT gene that has been seen as an important one is rs4633

  • The rs4633 has been associated with body mass index, more concretely allele T has been associated with increased BMI. So, individuals with genotype T/T and T/C on average might have somewhat hight BMI.


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