Other entities represented in this entry:
HGNC Approved Gene Symbol: COMT
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38): 22:19,941,772-19,969,975 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.21 | {Panic disorder, susceptibility to} | 167870 | ?Autosomal dominant | 3 |
| {Schizophrenia, susceptibility to} | 181500 | Autosomal dominant | 3 |
Catechol-O-methyltransferase (COMT; EC 2.1.1.6) is one of the major mammalian enzymes involved in the metabolic degradation of catecholamines (summary by Gogos et al., 1998). COMT catalyzes the transfer of a methyl group from S-adenosyl-methionine (SAM) to a hydroxyl group on a catechol nucleus (e.g., dopamine, norepinephrine, or catechol estrogen) (summary by Chen et al., 2004).
Lundstrom et al. (1991) isolated cDNA clones for COMT from a human placenta cDNA library using synthetic oligonucleotides as probes. The clones contained an open reading frame that potentially coded for a 24.4-kD polypeptide, presumably corresponding to the cytoplasmic form of COMT. DNA analysis suggested that the human, as well as the rat, dog, and monkey, has 1 gene for COMT.
Wilson et al. (1984) excluded tight and close linkage of COMT with 21 and 15 loci, respectively. A lod score of 1.27 at theta = 0.1 was found between COMT and phosphogluconate dehydrogenase (PGD; 172200), which is on chromosome 1.
In studies of mouse-human cell hybrids with a method permitting direct detection of COMT isozymes in autoradiozymograms, Brahe et al. (1986) located the COMT gene on human chromosome 22. By study of DNAs from a panel of human-hamster somatic cell hybrid lines, Grossman et al. (1991, 1992) mapped COMT to 22q11.1-q11.2. Winqvist et al. (1991) assigned COMT to 22q11.2 by means of Southern blot analysis of somatic cell hybrids and chromosomal in situ hybridization. They concluded that COMT is located proximal to the breakpoint cluster region (BCR) involved in chronic myeloid leukemia (151410). Bucan et al. (1993) mapped the homologous murine gene to chromosome 16, where, as in the human, it is closely linked to the lambda light chain genes.
During experiments aimed at building a contiguous group of YACs spanning 22q11, Dunham et al. (1992) found that the HP500 sequence often deleted in the velocardiofacial syndrome (VCFS; 192430) was located within the same 450-kb YAC as the COMT gene. They raised the question of whether low COMT might be responsible for psychotic illness, which is a feature of the VCF syndrome in adolescents and adults (Shprintzen et al., 1992).
Gustavson et al. (1973, 1982) reported that COMT activity was about 40% higher in Down syndrome children than in normal controls. They attributed this to dosage effect owing to a presumed location of the COMT gene on chromosome 21. Brahe et al. (1986) studied the expression of human COMT in interspecies somatic cell hybrids and found 27% discordance between human chromosome 21 and human COMT, suggesting that an assignment of the human COMT gene to chromosome 21 was very unlikely.
COMT Activity Polymorphism
Catechol-O-methyltransferase catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine. This O-methylation results in one of the major degradative pathways of the catecholamine transmitters. In addition to its role in the metabolism of endogenous substances, COMT is important in the metabolism of catechol drugs used in the treatment of hypertension, asthma, and Parkinson disease. In blood COMT is found mainly in erythrocytes; in leukocytes it exhibits low activity. Weinshilboum and Raymond (1977) found bimodality for red cell catechol-O-methyltransferase activity. Of a randomly selected population, 23% had low activity. Segregation analysis of family data suggested that low activity is recessive. Scanlon et al. (1979) found that homozygotes have a thermolabile enzyme. Thus, the site of the low COMT mutation is presumably the structural locus. Levitt and Baron (1981) confirmed the bimodality of human erythrocyte COMT. They further showed thermolability of the enzyme in 'low COMT' samples, suggesting a structural alteration in the enzyme. Autosomal codominant inheritance of the gene coding for erythrocyte COMT activity was adduced by Floderus and Wetterberg (1981) and by Weinshilboum and Dunnette (1981). Gershon and Goldin (1981) concluded that codominant inheritance was consistent with the family data. Spielman and Weinshilboum (1981) suggested that the inheritance of red cell COMT is intermediate, or codominant, there being 3 phenotypes corresponding to the 3 genotypes in a 2-allele system. The COMT of persons with low enzyme activity is more thermolabile than that of persons with high activity.
Susceptibility to Obsessive-Compulsive Disorder
Karayiorgou et al. (1997, 1999) found an association between obsessive-compulsive disorder (OCD; 164230) and COMT; the homozygous low activity genotype of the COMT gene was associated with risk for OCD in males. Alsobrook et al. (2002) used a family-based genetic design in haplotype relative risk (HRR) and transmission disequilibrium test (TDT) analyses of the association between OCD and COMT. Fifty-six OCD probands and their parents were genotyped for the COMT locus. Analysis of allele and genotype frequencies between the proband genotypes and the control (parental nontransmitted) genotypes failed to replicate the previous finding of gender divergence and gave no evidence of overall association; furthermore, no linkage was detected by TDT. However, further analysis of the COMT allele frequencies by proband gender gave evidence of a mildly significant association with the low activity COMT allele in female probands (P = 0.049), but not in male probands.
Susceptibility to Schizophrenia
The COMT gene is a strong candidate for schizophrenia susceptibility (see 181500), owing to the role of COMT in dopamine metabolism and the location of the gene within the deleted region in VCFS, a disorder associated with high rates of schizophrenia. Shifman et al. (2002) found a highly significant association between schizophrenia and a COMT haplotype in a large case-control sample in Ashkenazi Jews. In addition to the functional val158-to-met polymorphism (116790.0001; rs4680), this haplotype included 2 noncoding SNPs at either end of the COMT gene (rs737865 and rs165599). With this background information, Bray et al. (2003) postulated that the COMT susceptibility haplotype is associated with low COMT expression. To test their hypothesis, they applied quantitative measures of allele-specific expression using mRNA from human brain. They demonstrated that COMT is subject to allelic differences in expression in human brain and that the COMT haplotype implicated in schizophrenia by Shifman et al. (2002) is associated with lower expression of COMT mRNA. They also showed that the 3-prime flanking region SNP that in the study of Shifman et al. (2002) gave greatest evidence for association with schizophrenia is transcribed in human brain and exhibits significant differences in allelic expression, with lower relative expression of the associated allele. They concluded that the haplotype implicated in schizophrenia susceptibility is likely to exert its effect, directly or indirectly, by downregulating COMT expression.
In 38 populations representing all major regions of the world, Palmatier et al. (2004) studied the frequency of the schizophrenia-associated COMT haplotype reported by Shifman et al. (2002) as well as a 7-site COMT haplotype. Their results supported the relevance of the COMT P2 promoter to schizophrenia. The population data showed that the schizophrenia-associated haplotype varies significantly in frequency around the world and has significant heterogeneity when other markers in COMT are also considered.
Lee et al. (2005) screened for 17 known polymorphisms in the COMT gene in 320 Korean patients with schizophrenia and 379 controls. They identified a positive association of schizophrenia with a nonsynonymous SNP (rs6267) at codon 72/22 (membrane/soluble-bound form) causing an ala-to-ser substitution (A72S; 116790.0002). Lee et al. (2005) showed that the A72S substitution was correlated with reduced COMT enzyme activity, and their results supported previous reports that the COMT haplotypes implicated in schizophrenia are associated with low COMT expression.
Susceptibility to Anorexia Nervosa
Frisch et al. (2001) found an association between anorexia nervosa (AN; 606788) and the COMT val158 allele (V158M; 116790.0001) in a family-based study of 51 Israeli-Jewish AN trios. Gabrovsek et al. (2004) could not replicate this finding in a combined sample of 372 European AN families, suggesting that the findings of Frisch et al. (2001) were specific to a particular population and that val158 is in linkage disequilibrium with other molecular variations in the COMT gene, or its vicinity, which were the direct cause of genetic susceptibility to anorexia nervosa. Michaelovsky et al. (2005) studied 85 Israeli-Jewish AN trios, including the original sample of Frisch et al. (2001), comprising 66 anorexia nervosa restricting (AN-R) and 19 binge-eating/purging patients. They performed a family-based TDT analysis for 7 SNPs in the COMT-ARVCF (602269) region including the V158M polymorphism. TDT analysis of 5-SNP haplotypes in the AN-R group revealed overall statistically significant transmission disequilibrium for 'haplotype B' (COMT 186C, 408G, 472G [val158] and ARVCF 659C[pro220] and 524T[val175]) (P less than 0.001), while 'haplotype A' (COMT 186T, 408C, 472A[met158] and ARVCF 659T[leu220] and 524C[ala175]) was preferentially not transmitted (P = 0.01). Haplotype B was associated with increased risk (RR of 3.38), while haplotype A exhibited a protective effect (RR of 0.40) for AN-R. Preferential transmission of the risk alleles and haplotypes from parents was mostly contributed by fathers.
Associations Pending Confirmation
Sweet et al. (2005) conducted a study to determine if COMT genetic variation was associated with a risk of psychosis in Alzheimer disease (AD; see 114300). The study included a case-control sample of 373 individuals diagnosed with AD with or without psychosis. Subjects were characterized for alleles at 3 loci previously associated with schizophrenia, rs737865, rs4680, and rs165599, and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Single-locus and haplotype tests of association were conducted. Logit models were used to examine independent and interacting effects of alleles at the associated loci and all analyses were stratified by sex. In female subjects, rs4680 demonstrated a modest association with AD plus psychosis; rs737865 demonstrated a trend towards an association. There was a highly significant association of AD plus psychosis with a 4-locus haplotype, which resulted from additive effects of alleles at rs4680 and ERE6/rs737865 (the latter were in linkage disequilibrium). In male subjects, no single-locus test was significant, although a strong association between AD with psychosis and the 4-locus haplotype was observed. That association appeared to result from interaction of the ERE6/rs737865, rs4680, rs165599 loci. Genetic variation in COMT was associated with AD plus psychosis and thus appears to contribute to psychosis risk across disorders.
Three common haplotypes of the human COMT gene are divergent at 2 synonymous and 1 nonsynonymous position (Diatchenko et al., 2005). One is rs4633, which is either a C or T, but both code for a histidine at amino acid 62; the other is rs4818, which can be a G or C, but both code for a leucine at nucleotide 136; the nonsynonymous haplotype is represented by rs4680, a met158-to-val change change (116790.0001). Nackley et al. (2006) noted that the 3 common haplotypes code for differences in COMT enzymatic activity and are associated with pain sensitivity. Haplotypes divergent in synonymous changes exhibited the largest difference in COMT enzymatic activity, due to a reduced amount of translated protein. The major COMT haplotypes varied with respect to mRNA local stem-loop structures, such that the most stable structure was associated with the lowest protein levels and enzymatic activity. Site-directed mutagenesis that eliminated the stable structure restored the amount of translated protein. Nackley et al. (2006) concluded that their data highlighted the functional significance of synonymous variations and suggested the importance of haplotypes over SNPs for analysis of genetic variations.
Gogos et al. (1998) generated mice deficient for COMT. They measured the basal concentrations of brain catecholamines in the striatum, frontal cortex, and hypothalamus of adult male and female mutants and analyzed locomotor activity, anxiety-like behaviors, sensorimotor gating, and aggressive behavior. Mutant mice demonstrated sexually dimorphic and region-specific changes of dopamine levels, notably in the frontal cortex. Homozygous COMT-deficient female (but not male) mice displayed impairment in emotional reactivity in the dark/light exploratory model of anxiety. Furthermore, heterozygous COMT-deficient male mice exhibited increased aggressive behavior. Gogos et al. (1998) concluded that their results provided conclusive evidence for an important sex- and region-specific contribution of COMT in the maintenance of steady-state levels of catecholamines in the brain and suggested a role for COMT in some aspects of emotional and social behavior in mice.
Kanasaki et al. (2008) showed that pregnant mice deficient in COMT showed a preeclampsia-like phenotype resulting from absence of 2-methoxyestradiol (2-ME), a natural metabolite of estradiol that is elevated during the third trimester of normal human pregnancy. Administration of 2-ME ameliorated all preeclampsia-like features without toxicity in Comt -/- pregnant mice and suppressed placental hypoxia, Hif1a (603348) expression, and soluble Flt1 (165070) elevation. The levels of COMT and 2-ME were significantly lower in women with severe preeclampsia. Kanasaki et al. (2008) suggested that Comt-null mice may provide a model for preeclampsia and that 2-ME may serve as a diagnostic marker as well as a therapeutic agent for preeclampsia.
Duplications of human chromosome 22q11.2 (608363) are associated with elevated rates of mental retardation, autism, and many other behavioral phenotypes. Suzuki et al. (2009) determined the developmental impact of overexpression of an approximately 190-kb segment of human 22q11.2, which includes the genes TXNRD2 (606448), COMT, and ARVCF (602269), on behaviors in bacterial artificial chromosome (BAC) transgenic mice. BAC transgenic mice and wildtype mice were tested for their cognitive capacities, affect- and stress-related behaviors, and motor activity at 1 and 2 months of age. BAC transgenic mice approached a rewarded goal faster (i.e., incentive learning), but were impaired in delayed rewarded alternation during development. In contrast, BAC transgenic and wildtype mice were indistinguishable in rewarded alternation without delays, spontaneous alternation, prepulse inhibition, social interaction, anxiety-, stress-, and fear-related behaviors, and motor activity. Compared with wildtype mice, BAC transgenic mice had a 2-fold higher level of COMT activity in the prefrontal cortex, striatum, and hippocampus. Suzuki et al. (2009) suggested that overexpression of this 22q11.2 segment may enhance incentive learning and impair the prolonged maintenance of working memory, but has no apparent affect on working memory per se, affect- and stress-related behaviors, or motor capacity. High copy numbers of this 22q11.2 segment may contribute to a highly selective set of phenotypes in learning and cognition during development.
COMT inactivates catecholamines and catechol drugs such as L-DOPA. Weinshilboum and Raymond (1977), Spielman and Weinshilboum (1981), and others demonstrated that the level of COMT enzyme activity is genetically polymorphic in human red blood cells (RBCs) and liver, with a trimodal distribution of low, intermediate, and high levels of activity. This genetic polymorphism results in a 3- to 4-fold difference in COMT activity in RBCs and liver. Segregation analysis of data from family studies demonstrated that the pattern of inheritance is consistent with the presence of autosomal codominant alleles. The polymorphism was also associated with individual variation in COMT thermal instability. Lachman et al. (1996) showed that this polymorphism is due to a G-to-A transition at codon 158 of the COMT gene, resulting in a valine-to-methionine (V158M) substitution. The 2 alleles could be identified with a PCR-based restriction fragment length polymorphism analysis using the restriction enzyme NlaIII.
Lachman et al. (1996) studied patients with velocardiofacial syndrome (VCFS; 192430), a relatively common congenital disorder associated with typical facial appearance, cleft palate, cardiac defects, and learning disabilities. Most patients have an interstitial deletion on 22q11. In addition to physical abnormalities, a variety of psychiatric illnesses have been reported in patients with VCFS, including schizophrenia (181500), bipolar disorder (125480), and attention deficit hyperactivity disorder. The psychiatric manifestations of VCFS could be due to haploinsufficiency of a gene or genes within 22q11, and since the COMT gene maps to this region, it is a candidate. Homozygosity for 158met leads to a 3- to 4-fold reduction in enzymatic activity, compared with homozygosity for 158val. Lachman et al. (1996) reported that in the population of patients with VCFS, there was an apparent association between the low-activity allele, 158met, and the development of bipolar spectrum disorder and, in particular, a rapid-cycling form.
Comorbid panic disorder may define a subtype of bipolar disorder and may influence the strength of association between bipolar disorder and candidate genes involved in monoamine neurotransmission. Rotondo et al. (2002) studied the frequency of the V158M polymorphism, the 5-HTTLPR polymorphism of the serotonin transporter SLC6A4 (182138.0001), and a splice site polymorphism (IVS7+218C-A) of tryptophan hydroxylase (TPH; 191060) in a case-control association study of bipolar disorder patients with or without lifetime panic disorder. They compared results from DNA extracted from blood leukocytes of 111 unrelated subjects of Italian descent meeting DSM-III-R criteria for bipolar disorder, including 49 with and 62 without comorbid lifetime panic disorder, with those of 127 healthy subjects. Relative to the comparison subjects, subjects with bipolar disorder without panic disorder, but not those with comorbid bipolar disorder and panic disorder, showed significantly higher frequencies of the COMT met158 and the short 5-HTTLPR alleles. No statistical significance was found between the bipolar disorder groups and the TPH polymorphism. Rotondo et al. (2002) concluded that bipolar disorder without panic disorder may represent a more homogeneous form of illness and that variants of the COMT and SLC6A4 genes may influence clinical features of bipolar disorder.
Graf et al. (2001) treated 5 patients with the 22q11.2 deletion syndrome, the 158met polymorphism, and neuropsychiatric illness with a trial of metyrosine. They suggested that the presence of the 158met variant on the nondeleted allele, known to be associated with decreased enzyme activity, leads to increased catecholamine levels and could contribute to neuropsychiatric manifestations. Metyrosine, a competitive inhibitor of tyrosine hydroxylase, lowers the concentration of homovanillic acid, presumably by decreasing brain dopamine. Four of the 5 patients treated experienced subjective improvements in overall well-being.
Hoda et al. (1996) found no relationship between this common polymorphism and susceptibility to idiopathic Parkinson disease.
Syvanen et al. (1997) likewise demonstrated a val158-to-met change as the basis for the high-activity thermostable and low-activity thermolabile forms of the COMT gene. In the Finnish population, they found that the 2 COMT alleles are equally distributed. No statistically significant difference in the frequencies of the COMT alleles were found when comparing the normal population with a sample of 158 Finnish patients with Parkinson disease.
Alcoholism (103780) has been classified into 2 subtypes. Type 2 alcoholism is associated with early onset, high novelty seeking, and impulsive antisocial behavior. Most alcoholics can be classified as type 1, which is characterized by late onset (over 25 years) and no prominent antisocial behavior (Cloninger, 1995). In vivo brain imaging studies in humans have indicated that a dysfunction in dopaminergic neurotransmission occurs in type 1 but not type 2 alcoholics. Since COMT has a crucial role in the metabolism of dopamine, it was suggested that the common functional genetic polymorphism in the COMT gene, which results in 3- to 4-fold difference in COMT enzyme activity (Lachman et al., 1996; Syvanen et al., 1997), may contribute to the etiology of alcoholism. Since ethanol-induced euphoria is associated with the rapid release of dopamine in limbic areas, it was considered conceivable that subjects who inherited the allele encoding the low-activity COMT variant would have a relatively low dopamine inactivation rate, and therefore would be more vulnerable to the development of ethanol dependence. Tiihonen et al. (1999) tested this hypothesis among type 1 (late-onset) alcoholics. Two independent Finnish populations were studied, 1 in Turku (67) and 1 in Kuopio (56). The high (H)- and low (L)-activity COMT genotype and allele frequencies were compared with previously published data from Finnish blood donors and race- and gender-matched controls. The frequency of the L allele was markedly higher among the patients in both groups when compared with the general population. The L allele frequency was significantly higher among alcoholics when compared with controls (P = 0.009). The estimate for population etiologic (attributable) fraction for the LL genotype in alcoholism was 13.3% (95% CI = 2.3-25.7%).
Egan et al. (2001) examined the relationship of this COMT polymorphism (which they referred to as VAL108/158MET), which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected sibs, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance in frequency of perseverative errors. The load of the low activity met allele predicted enhanced cognitive performance. Egan et al. (2001) then examined the effect of COMT genotype on prefrontal physiology during a working memory task in 3 separate subgroups assayed with functional MRI. The met allele load consistently predicted a more efficient physiologic response in prefrontal cortex. In transmission disequilibrium test of 104 trios, Egan et al. (2001) found a significant increase in transmission of the val allele to the schizophrenic offspring. Egan et al. (2001) concluded that the COMT val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology and by this mechanism slightly increases risk for schizophrenia.
Shifman et al. (2002) reported the results of a study of COMT as a candidate gene for schizophrenia, using a large sample size (the largest case-control study performed to that time); a relatively well-defined and homogeneous population (Ashkenazi Jews); and a stepwise procedure in which several single nucleotide polymorphisms (SNPs) were scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. They found a highly significant association between schizophrenia and a COMT haplotype; P = 9.5 x 10(-8).
Glatt et al. (2003) evaluated the collective evidence for an association between the val158/108met polymorphism (codon 158 of the membrane-bound form; codon 108 of the soluble form) of the COMT gene and schizophrenia by performing a separate metaanalysis of 14 case-control and 5 family-based studies published between 1996 and 2002. Overall, the case-control studies showed no indication of an association between either allele and schizophrenia, but the family-based studies found modest evidence implicating the val allele in schizophrenia risk. Glatt et al. (2003) concluded that the family-based studies might be more accurate since this method avoids the pitfalls of population stratification. They suggested that the val allele may be a small but reliable risk factor for schizophrenia for people of European ancestry but that its role in Asian populations remained unclear.
Fan et al. (2005) conducted a large-scale association study plus metaanalysis of the COMT val/met polymorphism and risk of schizophrenia in 862 patients and 928 healthy control subjects from a Han Chinese population. No significant differences were found in allele or genotype frequencies between patients and normal control subjects, although a nonsignificant overrepresentation of the val allele in schizophrenia patients (OR = 1.09, 95% CI = 0.94-1.26) was suggested. The metaanalysis provided no significant evidence for an association between schizophrenia and the val allele in Asian or European populations.
Malhotra et al. (2002) studied 73 healthy individuals who took the Wisconsin Card Sorting Test and were genotyped for the val158-to-met polymorphism. ANOVA analysis revealed that the met/met group made significantly fewer perseverative errors than either the met/val group (p = 0.02) or the val/val group (p = 0.02). There were no significant differences between the performances of the met/val and val/val groups. The findings provided evidence that reduced COMT function is associated with improved cognitive performance.
To determine if the V158M polymorphism influences prefrontal cognitive function and increases the risk for schizophrenia, Rosa et al. (2004) genotyped 89 sib pairs discordant for psychosis for this polymorphism and assessed the sib pairs with the Wisconsin Card Sorting Test. In healthy sibs, a linear relationship was seen in which performance on the Wisconsin Card Sorting Test was associated in an allele dosage fashion with COMT genotype (val/val vs other genotypes, p = 0.007); however, this association was not observed in patients with schizophrenia. Furthermore, there was no evidence of genetic association with psychosis.
In a case-control study of 320 Korean patients with schizophrenia and 379 controls, Lee et al. (2005) found that the val/met polymorphism was not associated with an increased risk of schizophrenia (OR = 0.88, 95% CI = 0.64-1.21, p = 0.43).
Tsai et al. (2006) studied the transmission of the COMT val/met polymorphism in 223 trios consisting of Chinese patients with schizophrenia and their biologic parents. Using the transmission disequilibrium test, they found no significant difference between transmitted and nontransmitted allele frequencies for this polymorphism.
To study the association of the COMT val/met polymorphism with schizophrenia, Williams et al. (2005) studied 2,800 individuals including nearly 1,200 individuals with schizophrenia from case-control and family-based European association samples. No support was found for the hypotheses that the polymorphism influences susceptibility to schizophrenia in general or in Ashkenazi or Irish subjects.
Munafo et al. (2005) studied the association of the COMT val108/158met allele with schizophrenia by conducting a metaanalysis of 18 studies published between 1996 and 2003. When all studies were included in a metaregression, there was evidence for a significant association of the COMT val allele frequency with schizophrenia case status and a significant main effect of ancestry. However, the interaction of the COMT val allele frequency and ancestry was also significant. When Munafo et al. (2005) included only studies that reported allele frequencies that did not depart significantly from Hardy-Weinberg equilibrium among controls, these effects were no longer significant. Thus, the results of the metaanalysis did not support an association between the COMT val allele and schizophrenia case status and did not indicate that an association may be moderated by ancestry.
Woo et al. (2002) studied 51 patients meeting DSM-IV criteria for panic disorder and 45 healthy comparison subjects for the V158M polymorphism. The frequency of the met/met genotype was significantly higher in patients with panic disorder than in healthy subjects (19.6% vs 2.2%). Furthermore, panic disorder was significantly associated with the met allele (38.2% vs 18.9%). Patients with panic disorder who had the met/met genotype had a poorer treatment response than those with other genotypes. Woo et al. (2002) concluded that COMT activity might be related to susceptibility to panic disorder and treatment response to medications.
Wu et al. (2001) analyzed 224 Taiwanese patients with Parkinson disease (168600) for MAOB intron 13 G (309860) and COMT L (V158M) polymorphisms and found that the MAOB G genotype (G in men, G/G in women) was associated with a 2.07-fold increased relative risk for PD, an association which was stronger for men than for women. Although COMT polymorphism alone was not associated with an increased risk for PD, when it was considered in conjunction with the MAOB G genotype, there was a 2.4-fold increased relative risk for PD. In men, the combined alleles, MAOB G and COMT L, increased the relative risk for PD to 7.24. Wu et al. (2001) suggested that, in Taiwanese, the development of PD may be related to the interaction of 2 or more genes involved in dopamine metabolism.
The functional V158M variant represents an exon 4 SNP that is detected as an NlaIII restriction site polymorphism. It is polymorphic in populations around the world (Palmatier et al., 1999). DeMille et al. (2002) described a 4-site haplotype spanning 28 kb and effectively encompassing the COMT gene.
Avramopoulos et al. (2002) genotyped 379 healthy 18- to 24-year-old male individuals who had completed the Perceptual Aberration Scale (PAS), Schizotypal Personality Questionnaire (SPQ), and Aggression Questionnaire (AQ). Self-reported schizotypy scores were significantly related to the COMT val158-to-met polymorphism (P = 0.028 for the PAS and P = 0.015 for the SPQ). Individuals homozygous for the high activity allele showed the highest scores. No significant findings were seen using the AQ.
Suicidal behavior is often correlated with other-directed aggression, which is believed to be partially mediated by catecholaminergic neurotransmission. Rujescu et al. (2003) examined the influence of the V158M polymorphism on suicidal behavior and anger-related traits. By Taq polymerase digestion of PCR products, they genotyped 149 German suicide attempters and 328 German control subjects. There was no overall difference in allele/genotype frequency between patients and control subjects. However, the low activity L allele was overrepresented in violent suicide attempters (62% vs 51%). LL carriers expressed their anger more outwardly versus HH carriers who expressed it more inwardly, and they reported more state anger, as assessed by the State-Trait Anger Expression Inventory. Rujescu et al. (2003) interpreted these findings as supporting the hypothesis that this functional polymorphism may modify the phenotype of suicide attempts and anger-related traits.
Zubieta et al. (2003) examined the influence of the V158M polymorphism, which affects the metabolism of catecholamines, on the modulation of responses to sustained pain in humans. Individuals homozygous for the M158 allele showed diminished regional mu-opioid system (see 600018) responses to pain compared with heterozygotes. These effects were accompanied by higher sensory and affective ratings of pain and a more negative internal affective state. Opposite effects were observed in V158 homozygotes. Zubieta et al. (2003) concluded that the COMT V158M polymorphism influences the human experience of pain and may underlie interindividual differences in the adaptation and responses to pain and other stressful stimuli.
The clinical effects of amphetamine are quite variable, from positive effects on mood and cognition in some individuals, to negative responses in others, perhaps related to individual variations in monoaminergic and monoamine system genes. Mattay et al. (2003) found that amphetamine enhanced the efficiency of prefrontal cortex function assayed with functional MRI during a working memory task in subjects with the high enzyme activity val/val genotype, who presumably have relatively less prefrontal synaptic dopamine. In contrast, in subjects with the low activity met/met genotype who tend to have superior baseline prefrontal function, the drug had no effect on cortical efficiency at low-to-moderate working memory load and caused deterioration at high working memory load. The data illustrated an application of functional neuroimaging and extended basic evidence of an inverted-'U' functional-response curve to increasing dopamine signaling in the prefrontal cortex. Further, individuals with the met/met catechol O-methyltransferase genotype appeared to be at increased risk for an adverse response to amphetamine.
In COS-1 and HEK293 cells, Shield et al. (2004) transiently expressed wildtype and thr52 and met108 variants of COMT. The thr52 variant had no significant change in level of COMT activity, but there was a 40% decrease in the level of activity in cells transfected with the met108 variant. The met108 variant displayed a 70 to 90% decrease in immunoreactive protein when compared with wildtype, but there was no significant change in the level of immunoreactive protein for thr52. A significant decrease in the level of immunoreactive protein was also found in hepatic biopsy samples from patients homozygous for the met108 allele. Shield et al. (2004) concluded that the decreased level of activity of the met108 allele appeared to be due to a reduced COMT protein level.
In a large sample (n = 108) of postmortem human prefrontal cortex tissue, which expresses predominantly the membrane-bound isoform of COMT, Chen et al. (2004) studied the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using RT-PCR analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation). They found that the common coding SNP V158M significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. Using site-directed mutagenesis of mouse COMT cDNA followed by in vitro translation, they found that the conversion of leu at the homologous position into met or val progressively and significantly diminished enzyme activity. Thus, although Chen et al. (2004) could not exclude a more complex genetic basis for functional effects of COMT, val158 appeared to be a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.
Using multimodal neuroimaging techniques to analyze 24 healthy individuals, Meyer-Lindenberg et al. (2005) found that 11 carriers of the val108/158 allele had significantly higher midbrain F-DOPA uptake rates compared to 13 homozygous met108/158 carriers, indicating decreased dopamine synthesis in met carriers. During a working memory challenge test, the 2 genotypes were associated with inverse differences in regional blood flow in the prefrontal cortex as related to midbrain F-DOPA uptake, reflecting greater cortical extracellular dopamine in met homozygotes. The findings suggested a dopaminergic 'tuning' mechanism in the prefrontal cortex during cognitive processing and indicated a link between cortical and subcortical dopaminergic activity.
Thapar et al. (2005) noted that early-onset antisocial behavior accompanied by ADHD is a clinically severe variant of antisocial behavior with a poor outcome. In 240 British children with ADHD or hyperkinetic disorder, they studied the V158M SNP and the effects of birth weight, which is an environmentally influenced index. A comprehensive standardized assessment including measures of antisocial behavior and IQ was conducted. The val/val genotype (P = 0.002) and lower birth weight (P = 0.002) were associated with increased symptoms of conduct disorder and a significant gene-environment interaction (P = 0.006) was also confirmed.
Bruder et al. (2005) examined the relation of V158M genotype to performance on a battery of working memory tests that assessed different cognitive operations. A total of 4,002 healthy adults were tested for working memory tasks: Spatial Delayed Response, Word Serial Position Test, N-back, and Letter-Number Sequencing. A subsample of 246 individuals was tested on the Wisconsin Card Sorting Test. Letter-Numbering Sequencing was the only working memory test that showed expected differences with the met/met group showing the best performance and the val/val group reporting the poorest performance. The met/met group also performed better than the val/val group on the Wisconsin Card Sorting Test. Bruder et al. (2005) concluded that COMT genotype was not associated with performance on tests measuring simple storage, maintenance of temporal order, or updating of information in working memory but was associated with higher-order components of processing.
Baker et al. (2005) studied 2 hypotheses: first, that individuals with 22q11 deletion syndrome (see 188400 and 192430) would manifest specific cognitive and neurophysiologic abnormalities in common with individuals at high risk for schizophrenia in the general population; and second, that the COMT val108/158met polymorphism would modify the severity of endophenotypic features. Adolescents and young adults with 22q11 deletion syndrome, aged 13-21, were compared with age- and IQ-matched control subjects on measures that were associated with risk for idiopathic schizophrenia. These individuals displayed poorer verbal working memory and expressive language performance than control subjects. Auditory mismatch negativity event-related potentials were reduced at frontal electrodes but intact at temporal sites. The presence of the COMT val108/158met allele on the single intact chromosome 22 was associated with more marked auditory mismatch negativity amplitude reduction and poorer neuropsychologic performance. Neither allele influenced psychiatric symptoms.
Patients with DiGeorge syndrome (188400) are hemizygous for the COMT gene. In a study of 21 nonpsychotic DiGeorge syndrome patients aged 7 to 16 years, Shashi et al. (2006) found that those carrying the met158 allele performed better on tests of general cognitive ability and on a specific test of prefrontal cognition compared to those with the val158 allele. Glaser et al. (2006) tested measures of executive function, IQ, and memory in 34 children and young adults with the 22q11.2 microdeletion (14 hemizygous for val158 and 30 for met158). No significant differences were detected between met- and val-hemizygous participants on measures of executive function. The groups did not differ on full-scale, performance, and verbal IQ or on verbal and visual memory. Glaser et al. (2006) suggested that either the COMT polymorphism has a small effect on executive function in 22q11.2 deletion syndrome or no effect exists at all.
Stolk et al. (2007) determined the genotype of the val158-to-met polymorphism in 2,515 men and 3,554 women from the Rotterdam Study, a population-based cohort study of individuals aged 55 and older. Male carriers of the met158 allele had an increased risk for osteoporotic fractures (hazard ratio = 1.6; 95% CI, 1.0-2.4) and for fragility fractures (hazard ratio = 2.7; 95% CI, 1.3-5.9), with evidence for a dominant effect. Adjustments for age, height, weight, and bone mineral density (BMD) did not change the risk estimates. Stolk et al. (2007) concluded that the COMT V158M polymorphism is associated with fracture risk in elderly men, through a mechanism independent of BMD.
Zalsman et al. (2005) studied the relationship of MAOA promoter (uVNTR; 309850.0002) and COMT missense (V158M) polymorphisms to CSF monoamine metabolite levels in a psychiatric sample of 98 Caucasians who were assessed for axis I and II diagnoses. CSF was obtained by lumbar puncture and the relationships of the 2 polymorphisms to monoamine metabolites (HVA, 5-HIAA, and MHPG) were examined. The higher-expressing MAOA-uVNTR genotype was associated with higher CSF-HVA levels in males (N = 46) (195.80 pmol/ml, SD = 61.64 vs 161.13, SD = 50.23, respectively; p = 0.042). No association was found with the diagnosis. The COMT V158M polymorphism was not associated with CSF monoamine metabolite levels.
L-DOPA, used to treat Parkinson disease (PD; 168600) is predominantly metabolized to the inactive 3-O-methyldopa by COMT. Entacapone is a COMT inhibitor that acts to prolong the half-life of L-DOPA and yields prolonged therapeutic benefits. The val158-to-met (V158M) polymorphism in the COMT gene confers increased (val) or decreased (met) COMT activity. In a randomized control trial of 33 PD patients, Corvol et al. (2011) found that those homozygous for the high-activity val158 allele had significantly increased COMT inhibition by entacapone and significantly better bioavailability of and clinical response to L-DOPA compared to patients homozygous for the low-activity met158 allele. The findings indicated that homozygosity for the val158 allele in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone in heterozygous patients was not studied.
Lee et al. (2005) screened for 17 known polymorphisms in the COMT gene in 320 Korean patients with schizophrenia and 379 controls. They identified a positive association of schizophrenia with a nonsynonymous SNP (rs6267) at codon 72/22 (membrane/soluble-bound form) causing an ala-to-ser substitution (A72S). With the ala/ala genotype as a reference group, they found that the combined genotype (ala/ser and ser/ser)-specific adjusted odds ratio was 1.82, suggesting 72ser as a risk allele for schizophrenia. Lee et al. (2005) showed that the A72S substitution was correlated with reduced COMT enzyme activity, and their results supported previous reports that the COMT haplotypes implicated in schizophrenia are associated with low COMT expression.
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