COMT
Catechol-O-methyltransferase
Gene Number: 1312
Location: 22q11.21
Key Functions: Dopamine metabolism, catecholamine degradation, cognitive control, pain modulation, stress resilience, and emotional regulation
COMT encodes catechol-O-methyltransferase, a critical enzyme responsible for the methylation and inactivation of catecholamines, including dopamine, norepinephrine, and epinephrine. By transferring a methyl group from S-adenosylmethionine (SAM) to catechol substrates, COMT regulates neurotransmitter turnover and modulates synaptic signaling dynamics throughout the central and peripheral nervous systems [R].
In the prefrontal cortex (PFC)—a brain region with low dopamine transporter (DAT) expression—COMT serves as the primary mechanism for dopamine clearance, directly influencing working memory, attention, cognitive flexibility, and executive function. Optimal COMT activity maintains balanced dopaminergic signaling, while deviations can lead to cognitive and affective variability [R].
A well-characterized single nucleotide polymorphism, Val158Met (rs4680), produces a valine (Val) to methionine (Met) substitution at codon 158, significantly altering enzymatic stability and activity. The Val variant confers higher enzymatic activity and faster dopamine degradation, often associated with enhanced stress resilience but reduced cognitive efficiency under low-stress conditions. Conversely, the Met variant results in lower COMT activity and elevated dopamine availability in the PFC, which may enhance cognitive performance but increase susceptibility to stress, anxiety, and dopaminergic dysregulation [R].
Beyond cognition, COMT influences pain perception, reward sensitivity, and emotional regulation by modulating catecholamine tone within limbic and cortical circuits. Altered COMT expression or function has been implicated in psychiatric and neurological conditions, including schizophrenia, bipolar disorder, anxiety, depression, and chronic pain syndromes [R].
By shaping the balance between dopaminergic efficiency and stress responsivity, COMT represents a key molecular determinant of individual variability in cognition, behavior, and mental health resilience.
SNP ID | Your Genotype | Alternative Alleles | Interpretation |
|---|---|---|---|
rs4680 | No matching variant or no valid DNA data | A | No interpretation available |
rs4633 | No matching variant or no valid DNA data | T | No interpretation available |
rs165599 | No matching variant or no valid DNA data | A | No interpretation available |
rs4680 (Core COMT SNP)
AA – Met/Met genotype reduces COMT activity by ~4×; linked to higher dopamine levels and greater stress sensitivity (R, R).
AG – Intermediate COMT activity; balanced dopamine clearance (R, R).
GG – Val/Val genotype increases COMT activity; lower dopamine levels; may improve stress resilience (R).
Functional effect: The A (Met) allele leads to reduced enzyme activity, resulting in higher synaptic dopamine, which can enhance cognitive function but also heighten stress vulnerability.
rs4633
TT – Greatest reduction in COMT mRNA; lower enzyme levels and significantly slower dopamine breakdown (R).
TC – Slight reduction in mRNA expression; moderate effect on dopamine clearance (R).
CC – Likely normal COMT mRNA expression (R).
Functional effect: This synonymous variant influences mRNA stability, with T alleles leading to lower COMT levels and altered dopamine metabolism.
rs165599
AA – Possibly better cognitive performance compared to GG (R).
AG – Intermediate function (R).
GG – Linked to poorer verbal memory and increased risk for certain psychiatric disorders (R).
Functional effect: Located in the 3′ UTR, this variant may alter gene regulation; G allele has been associated with cognitive deficits and psychiatric risk.
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