Catechol-O-methyl transferase (COMT) is an enzyme involved in O-methylation of catecholamines. The COMT gene is localized in chromosome 22, band q11.2, a chromosomal region of interest for psychosis and bipolar spectrum disorder. The human COMT gene contains six exons with the first two exons being noncoding. The expression of the COMT gene is controlled by two distinct promoters located in exon 3. 1


COMT has as a single domain α/β-folded structure in which eight α-helices are arranged around the central mixed β-sheet. The active site of COMT consists of the S-adenosyl-l-methionine- (AdoMet)-binding domain and the actual catalytic site. COMT is found in two forms in tissues, the longer form which is known as membrane-bound catechol-O-methyltransferase (MB-COMT) and is chiefly produced by nerve cells in the brain and a shorter form of the enzyme, soluble catechol-O-methyltransferase (S-COMT) which is present in other tissues, including the liver, kidneys, and blood.1


A common COMT polymorphism is characterized by valine-to-methionine (Val/Met) substitution at codons 108 and 158 of S-COMT and MB-COMT, respectively, resulting in a trimodal distribution of COMT, low (COMT LL), intermediate (COMT LH), and high (COMT HH) activities. This polymorphism is caused by autosomal codominant alleles and leads to 3- to 4-fold differences in COMT activity.  This polymorphism is usually referred to as the Val/Met locus, but is also known by the reference sequence identification code rs4680 (previously rs165688).1


A number of putative regulatory elements have been discovered in the COMT gene. As suggested by research, MB-COMT might exists in two forms which may be differentially affected by the Val/Met genotype. Thus, it is to be expected that there may be genetic complexity including possible gender specific effects. Polymorphism and haplotype frequencies at COMT have been shown to vary substantially across populations. 2


As a consequence of both its chromosomal location in a region of interest for psychosis and mood disorders and its function as an enzyme involved in catabolism of monoamines, COMT has been one of the most studied genes for psychiatric and neurological disorders. There is robust evidence that variation at COMT influences frontal lobe function and thereby cognitive function. Positional and functional evidence makes COMT gene a strong a priori candidate for involvement in psychosis and other psychiatric phenotypes. However, despite considerable research effort, results have not been consistent pertaining to a clear relationship between COMT genetic variation and psychiatric phenotypes. 2


Schizophrenia is the most substantially studied disorder followed by bipolar disorder for the Val/Met polymorphism. In schizophrenia, low COMT activity allele appears to have some association with aggressive and highly antisocial impulsive phenotype, while in obsessive-compulsive disorder affected persons follow various anxiety-reducing rituals, which seems to be correlated with low COMT activity allele. In Parkinson’s disease (PD), although, generally no association has been found between COMT alleles, however, some Japanese individuals with the low COMT activity allele may have an increased risk for PD. Low COMT activity allele has also been found more frequently in patients with breast cancer, particularly in women with menopausal symptoms. This phenomenon may be related to the decreased metabolism of catecholestrogens because COMT also metabolizes these compounds. 1