The COMT protein is coded by the gene
COMT. The gene is associated with allelic variants. The best-studied is
Val158Met. response to
antidepressant medications, and psychosis risk associated with
Alzheimer's disease. COMT has been studied as a potential gene in the pathogenesis of schizophrenia; however
meta-analyses find no association between the risk of schizophrenia and a number of polymorphisms, including Val158Met.
Val158Met polymorphism A functional
single-nucleotide polymorphism (a common normal variant) of the gene for catechol-
O-methyltransferase results in a
valine to
methionine mutation at position 158 (Val158Met)
rs4680. In vitro, the
homozygous Val variant metabolizes dopamine at up to four times the rate of its methionine counterpart. resulting in a 40% decrease (rather than 75% decrease) in functional enzyme activity. The lower rates of catabolism for the Met allele results in higher synaptic dopamine levels following neurotransmitter release, ultimately increasing dopaminergic stimulation of the postsynaptic neuron. Given the preferential role of COMT in prefrontal dopamine degradation, the Val158Met polymorphism is thought to exert its effects on cognition by modulating dopamine signaling in the
frontal lobes. The gene variant has been shown to affect
cognitive tasks broadly related to
executive function, such as set shifting, response inhibition, abstract thought, and the acquisition of rules or task structure. Comparable effects on similar cognitive tasks, the frontal lobes, and the neurotransmitter dopamine have also all been linked to
schizophrenia. It has been proposed that an inherited variant of
COMT is one of the genetic factors that may predispose someone to developing schizophrenia later in life. A more recent study cast doubt on the proposed connection between this gene and any alleged causal effect of cannabis on schizophrenia development. A non-synonymous
single-nucleotide polymorphism rs4680 was found to be associated with depressed factor of
Positive and Negative Syndrome Scale(PANSS) and efficiency of emotion in
schizophrenia subjects. It is increasingly recognised that allelic variation at the COMT gene are also relevant for emotional processing, as they seem to influence the interaction between prefrontal and limbic regions. Research conducted at the
Section of Neurobiology of Psychosis, Institute of Psychiatry, King's College London has demonstrated an effect of COMT both in patients with bipolar disorder and in their relatives, but these findings have not been replicated so far. The COMT Val158Met polymorphism also has a
pleiotropic effect on emotional processing. Furthermore, the polymorphism has been shown to affect ratings of
subjective well-being. When 621 women were measured with
experience sample monitoring, which is similar to mood assessment as response to beeping watch, the met/met form confers double the subjective mental sensation of well-being from a wide variety of daily events. The ability to experience reward increased with the number of Met alleles. Also, the effect of different genotype was greater for events that were felt as more pleasant. The effect size of genotypic moderation was quite large: Subjects with the Val/Val genotype generated almost similar amounts of subjective well-being from a 'very pleasant event' as Met/Met subjects did from a 'bit pleasant event'. Genetic variation with functional impact on cortical dopamine tone has a strong influence on reward experience in the flow of daily life.
Temporomandibular joint dysfunction Temporomandibular joint dysfunction (TMD) does not appear to be a classic genetic disorder, however variations in the gene that codes for COMT have been suggested to be responsible for inheritance of a predisposition to develop TMD during life. ==Nomenclature==