Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “COMT”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 523 records · Page 29Linked to original sources
PubMed1991

Effect of high single doses of levodopa and carbidopa on brain dopamine and its metabolites: modulation by selective inhibitors of monoamine oxidase and/or catechol-O-methyltransferase in the male rat.

The upper limits of striatal and hypothalamic dopamine formation and metabolism in the rat were defined after acute levodopa/carbidopa (100/100 mg/kg) in combination with MAO (clorgyline; 32 mg/kg or pargyline; 100 mg/kg) and/or COMT inhibitors (OR-462, OR-611, Ro 41-0960, 30 mg/kg). Striatal and hypothalamic dopa and 3-OMD levels increased several hundred times after levodopa/carbidopa treatment alone. Dopamine, DOPAC, HVA and 3-MT levels elevated also but noradrenaline and 5-HT did not. Clorgyline further increased 3-OMD, dopamine and 3-MT concentrations while DOPAC and HVA levels decreased. These changes were even more pronounced after pargyline. In the striatum, all COMT inhibitors (with levodopa/carbidopa) blocked 3-OMD formation but elevated neither dopamine nor DOPAC levels. OR-462 increased dopa levels. Only Ro 41-0960, the brain penetrating compound, blunted HVA levels. All three COMT inhibitors decreased high 3-OMD levels evoked by MAO inhibitors (+ levodopa/carbidopa). In pargyline-treated rats, COMT inhibitors did not alter dopamine, DOPAC or HVA levels but all of them decreased significantly 3-MT levels, particularly Ro 41-0960. Striatal dopamine levels increased maximally 6 times compared to those in the saline-treated controls. In the hypothalamus, COMT inhibitors decreased 3-OMD levels to 1/5-1/30 of those after levodopa/carbidopa alone. COMT inhibitors suppressed 3-OMD formation also in clorgyline and pargyline (+ levodopa/carbidopa) treated rats. After clorgyline, OR-611 and Ro 41-0960 increased high dopamine levels but only Ro 41-0960 suppressed HVA and 3-MT levels. None of the COMT inhibitors changed the high dopamine and low DOPAC levels after pargyline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Direct molecular haplotyping of multiple polymorphisms within exon 4 of the human catechol-O-methyltransferase gene by liquid chromatography-electrospray ionization time-of-flight mass spectrometry.

The applicability of ion-pair reversed-phase high-performance liquid chromatography hyphenated to electrospray ionization time-of-flight mass spectrometry (ICEMS) for the haplotyping of five SNPs (rs769223, rs4818, rs4986871, rs8192488, rs4680) located within exon 4 of the human catechol-O-methyltransferase (COMT, EC 2.1.1.6) gene is demonstrated. Two differently sized products of polymerase chain reaction--a 71-bp amplicon partially covering the sequence of a 124-bp amplicon--were used to determine unequivocally the allelic states of the single nucleotide polymorphisms linked on both chromosomes. The two amplicons were co-loaded onto the chromatographic column and simultaneously analyzed within a single gradient run. Using the described strategy, 101 individuals representing an Austrian population sample were typed. The obtained haplotype frequencies will serve as reference values in future association studies to examine the impact of the COMT gene on neuropsychiatric disorders. Additionally, two newly discovered polymorphic sites within the sequence of the COMT gene are described (a synonymous C>T mutation at the third position of the amino acid codon 99 in the soluble COMT protein or 149 in the membrane-bound COMT protein; a non-synonymous G>A substitution at the second position of the amino acid codon 95 in the soluble COMT protein or 145 in the membrane-bound-COMT protein).

Base Sequence↗
PubMed1998

Catechol-O-methyltransferase: variation in enzyme activity and inhibition by entacapone and tolcapone.

OBJECTIVE: The aim of this investigation was to study the variation of catechol-O-methyltransferase (COMT) activity in the human liver, duodenal mucosa and renal cortex, and to investigate the inhibition of COMT by entacapone and tolcapone. This study included 87 samples of human liver, 94 samples of the duodenum and 72 samples of the renal cortex. RESULTS: The activity of COMT was measured with 3,4-dihydroxybenzoic acid (242 micromol x l(-1)), the methyl acceptor substrate, and adenosyl-L-methionine (44 micromol x l(-1)), the methyl donor substrate. The hepatic activity of COMT activity was significantly higher in men than in women, whereas it was not sex-dependent in the duodenum or renal cortex. The activity of COMT varied 4.4-fold in the liver of men, 2.6-fold in the duodenum and 5.3-fold in the renal cortex. The median estimates of COMT activity were 577, 499, 103 and 159 pmol x min(-1) x mg(-1) in the liver of men and women, in the duodenum and in the renal cortex, respectively. CONCLUSION: Entacapone and tolcapone were powerful inhibitors of COMT and their IC50 estimates were 151 and 773 nM (P = 0.008), respectively, in the liver; consistent results were obtained with the other tissues.

Adult↗
PubMed2002

Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome.

Fibromyalgia syndrome (FS) is associated with a neuroendocrinal disorder characterized by abnormal function of the hypothalamic-pituitary-adrenal (HPA) axis, including hyperactive adrenocorticotropic hormone (ACTH) release and adrenal hyporesponsiveness. Catechol-O-methyltransferase (COMT) enzyme inactivates catecholamines and catecholamine-containing drugs. Polymorphism in the gene encodes for the COMT enzyme. For this study, the significance of COMT polymorphism was assessed in FS. There were three polymorphisms of the COMT gene: LL, LH, and HH. The analysis of COMT polymorphism was performed using polymerase chain reaction (PCR). Sixty-one patients with FS and 61 healthy volunteers were included in the study. Although no significant difference was found between LL and LH separately, the LL and LH genotypes together were more highly represented in patients than controls ( P=0.024). In addition, HH genotypes in patients were significantly lower than in the control groups ( P=0.04). There was no significant difference between COMT polymorphism and psychiatric status of the patients as assessed by several psychiatric tests ( P>0.05). In conclusion, COMT polymorphism is of potential pharmacological importance regarding individual differences in the metabolism of catechol drugs and may also be involved in the pathogenesis and treatment of FS through adrenergic mechanisms as well as genetic predisposition to FS.

Adult↗
PubMed1988

Inhibition of catechol-O-methyltransferase activity by two novel disubstituted catechols in the rat.

Catechol-O-methyltransferase (COMT) has an important role in the extraneuronal inactivation of catecholamine neurotransmitters and drugs with a catechol structure. Two novel COMT inhibitors, OR-462 and OR-486, were highly effective (IC50 = 18 and 12 nM, respectively) and selective in inhibiting COMT activity in vitro. Tyrosine hydroxylase was not inhibited until micromolar concentrations of these compounds were used: the IC50 values for OR-462 and OR-486 were 10 and 14 microM, respectively. The IC50 values for dopamine-beta-hydroxylase, dopa-decarboxylase and monoamine oxidase forms A and B were greater than 50 microM. In studies ex vivo oral OR-462 inhibited mainly the COMT activity in the duodenum while OR-486 inhibited COMT activity in the liver and red blood cells as well. Oral OR-462 did not penetrate into the brain in doses up to 30 mg/kg while the same dose of OR-486 had some effect on striatal COMT activity. When tested in combination with levodopa-carbidopa, orally administered OR-462 and OR-486 were more effective in reducing the formation of 3-O-methyldopa from levodopa than was the levodopa-carbidopa treatment alone. These results indicate that OR-462 and OR-486 are effective and long-lasting inhibitors of COMT activity.

Animals↗
PubMed1991

Catechol-O-methyltransferase and aromatic L-amino acid decarboxylase activities in human gastrointestinal tissues.

Human gastrointestinal samples from the corpus, antrum, bulbus, jejunum and ileum were assayed for soluble and membrane-bound catechol-O-methyltransferase (COMT) and aromatic L-amino acid decarboxylase (AADC) activity in vitro. The mean soluble COMT activities with 3,4-dihydroxybenzoic acid (DBA) and 3,4-dihydroxyphenylalanine (L-DOPA) as substrate were 70-242 and 70-174 pmol/min mg, respectively. The membrane-bound COMT activities ranged from 33 to 60 pmol/min mg in the different parts of the intestine. The AADC activities, measured with L-DOPA as the substrate, increased from 114 pmol/min mg in the corpus to 3488 pmol/min mg in the jejunum. The affinity of the soluble COMT was approximately 20 times higher for DBA (Km 15-19 microM) than for L-DOPA (Km 300-600 microM). The Km-values for L-DOPA of AADC and COMT were of the same order of magnitude. The specific COMT inhibitors, nitecapone and OR-611, effectively inhibited in vitro the human intestinal COMT activity. Nanomolar concentrations caused 50% inhibition with both DBA and L-DOPA as substrate.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed1994

General properties and clinical possibilities of new selective inhibitors of catechol O-methyltransferase.

1. The structure of catechol O-methyltransferase (COMT) has been recently characterized and a series of new and selective COMT inhibitors developed. 2. Entacapone, nitecapone and tolcapone are nitrocatechol-type potent COMT inhibitors in vitro (Ki in nanomolar range). They are also very selective for COMT and active in vivo even after oral administration. CGP 28014 is a pyridine derivative that is active only in vivo. 3. In animal studies, these compounds inhibit effectively the O-methylation of L-dopa, thus improving its bioavailability and brain penetration and potentiating its behavioural effects. 4. Entacapone and nitecapone have mainly a peripheral effect whereas tolcapone and CGP 28014 also inhibit O-methylation in the brain. 5. In man, entacapone, nitecapone and tolcapone all inhibit dose dependently the COMT activity in erythrocytes. These COMT inhibitors also decrease the amount of COMT dependent metabolites of adrenaline and noradrenaline in plasma. 6. In human volunteers, entacapone, tolcapone and CGP 28014 improve the bioavailability of L-dopa and inhibit the formation of 3-O-methyldopa. 7. In the first clinical studies in patients with Parkinson's disease, both entacapone and tolcapone potentiate and prolong the therapeutic effect of L-dopa.

Animals↗
PubMed1996

Purification methods of mammalian catechol-O-methyltransferases.

The protein purification strategies used for obtaining homogeneous rat and human soluble catechol-O-methyltransferase (S-COMT) polypeptides are reviewed. Expression and purification of recombinant rat and human S-COMT in Escherichia coli and for human S-COMT in baculevirus-infected insect cells made it possible to elucidate the S-COMT polypeptides in more detail. The application of these purification methods has allowed the crystallization of the rat S-COMT protein and the analysis of the kinetic properties of the enzyme in great detail. The availability of the pure S-COMT protein together with the structural data has also greatly enhanced the development of more potent COMT inhibitors.

Amino Acid Sequence↗
PubMed2004

Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications.

BACKGROUND: The gene encoding catechol-O-methyltransferase (COMT), an enzyme that regulates prefrontal cortex dopamine, contains a common functional polymorphism (val(108/158)met) that influences prefrontal cortex function in an allelic dose-dependent manner. A recent study reported that the COMT val(108/158)met polymorphism influences cognitive- and physiologic-related prefrontal cortex responses to antipsychotic treatment. The present study tested the effects of several COMT polymorphisms on the cognitive response to antipsychotic medication in patients with schizophrenia. METHODS: Twenty inpatients with schizophrenia or schizoaffective disorder (5 with the val-val genotype, 11 with val-met, and 4 with met-met) were administered cognitive tests at two time points: once after 4 weeks of treatment with antipsychotic medication and once after 4 weeks of placebo administration, according to a counterbalanced, double-blind, within-subject study design. RESULTS: Patients homozygous for the COMT met allele displayed significant improvement on the working memory task after treatment. Patients homozygous for the COMT val allele did not show working memory improvement with treatment. Other COMT polymorphisms were not associated with significant differences between treatment and placebo conditions. CONCLUSIONS: These results support other data suggesting that the COMT val(108/158)met polymorphism might be an important factor in the cognitive response to antipsychotic medication.

Adult↗
PubMed2006

Estrogen deficient male mice develop compulsive behavior.

BACKGROUND: Aromatase converts androgen to estrogen. Thus, the aromatase knockout (ArKO) mouse is estrogen deficient. We investigated the compulsive behaviors of these animals and the protein levels of catechol-O-methyltransferase (COMT) in frontal cortex, hypothalamus and liver. METHODS: Grooming was analyzed during the 20-min period immediately following a water-mist spray. Running wheel activity over two consecutive nights and barbering were analyzed. COMT protein levels were measured by Western analysis. RESULTS: Six-month old male but not female ArKO mice develop compulsive behaviors such as excessive barbering, grooming and wheel-running. Excessive activities were reversed by 3 weeks of 17beta-estradiol replacement. Interestingly, the presentation of compulsive behaviors is accompanied by concomitant decreases (p < .05) in hypothalamic COMT protein levels in male ArKO mice. These values returned to normal upon 17beta-estradiol treatment. In contrast, hepatic and frontal cortex COMT levels were not affected by the estrogen status, indicating region- and tissue-specific regulation of COMT levels by estrogen. No differences in COMT levels were detectable between female animals of both genotypes. CONCLUSIONS: This study describes the novel observation of a possible link between estrogen, COMT and development of compulsive behaviors in male animals which may have therapeutic implications in obsessive compulsive disorder (OCD) patients.

Animals↗
PubMed2006

Relationship of catechol-O-methyltransferase variants to brain structure and function in a population at high risk of psychosis.

BACKGROUND: There is growing evidence that the gene catechol-O-methyltransferase (COMT) is involved in the etiopathogenesis of schizophrenia. This study sought to clarify the effects of the COMT Val158Met polymorphism on brain structure, function, and risk of developing schizophrenia in a well-characterized cohort of individuals at high risk of schizophrenia for familial reasons. METHODS: In a sample of 78 people at high genetic risk of schizophrenia, the risk of progression to schizophrenia associated with the COMT Val allele was estimated. The relationship of the Val allele to brain structure and function was investigated using structural magnetic resonance imaging (sMRI) and functional magnetic resonance imaging (fMRI) data collected on the high-risk subjects before their disease outcome was known. RESULTS: The COMT Val allele increased the risk of schizophrenia in this cohort in a dose-dependent manner. Subjects with the COMT Val allele had reduced gray matter density in anterior cingulate cortex. In addition, there was evidence of increased activation in lateral prefrontal cortex and anterior and posterior cingulated, with increasing sentence difficulty in those with the COMT Val allele despite a similar level of performance. CONCLUSIONS: The COMT Val allele is associated with an increased risk of schizophrenia in subjects at increased familial risk, in whom it has demonstrable effects on prefrontal brain structure and function. These patterns of altered brain structure and function have previously been associated with schizophrenia in this and other samples.

Adolescent↗
PubMed2005

Contribution of catechol O-methyltransferase to the removal of accumulated interstitial catecholamines evoked by myocardial ischemia.

Catechol O-methyltransferase (COMT) plays an important role for clearance of high catecholamine levels. Although myocardial ischemia evokes similar excessive catecholamine accumulation, it is uncertain whether COMT activity is involved in the removal of accumulated catecholamines evoked by myocardial ischemia. We examined how COMT activity affects myocardial catecholamine levels during myocardial ischemia and reperfusion. We implanted a dialysis probe into the left ventricular myocardial free wall and measured dialysate catecholamines levels in anesthetized rabbits. Dialysate catecholamine levels served as an index of myocardial interstitial catecholamine levels. We introduced myocardial ischemia by 60 min occlusion of the main coronary artery. The ischemia-induced dialysate catecholamines levels were compared with and without the pretreatment with entacapone (COMT inhibitor, 10 mg/kg, i.p.). Acute myocardial ischemia progressively increased dialysate catecholamine levels. Acute myocardial ischemia increased dialysate norepinephrine (NE) levels (20,453+/-7186 pg/ml), epinephrine (EPI) levels (1724+/-706 pg/ml), and dopamine (DA) levels (1807+/-800 pg/ml) at the last 15 min of coronary occlusion. Inhibition of COMT activity by entacapone augmented the ischemia-induced NE levels (54,306+/-6618 pg/ml), EPI levels (2681+/-567 pg/ml), and DA (3551+/-710 pg/ml) levels at the last 15 min of coronary occlusion. Myocardial ischemia evoked NE, EPI, and DA accumulation in the myocardial interstitial space. The inhibition of COMT activity augmented these increments in NE, EPI, and DA. These data suggest that cardiac COMT activity influences on the removal of accumulated catecholamine during myocardial ischemia.

Animals↗
PubMed2002

Functional catechol-O-methyltransferase gene polymorphism and susceptibility to schizophrenia.

Genetic polymorphism of catechol-O-methyltransferase (COMT), involved in the degradation of catecholamine neurotransmitters, has been investigated as a candidate for modifier of susceptibility to development of schizophrenia. To address this issue further, we carried out a study in Korean schizophrenic patients and controls. The study population consisted of 103 Korean inpatients diagnosed as schizophrenic and their 103 age and sex matched controls. The patients were divided into two groups on the basis of history of aggressive behavior, family history of schizophrenia and related disorders, and age at onset of the disease. The COMT genotypes were determined by a PCR based method. No statistically significant overall associations between the COMT genotypes and risk of schizophrenia were observed. However, subjects with at least one low activity associated COMT-L allele showed a tendency of elevated risk for schizophrenia (OR=1.7, 95% CI=0.9-3.1) compared with those homozygous for the high activity associated COMT-H alleles. Moreover, when cases were stratified by family history of schizophrenia, a significant combined effect was seen: the cases with concurrent family history of schizophrenia and the COMT-L allele containing genotypes had an almost 4-fold (OR=3.9, 95% CI=1.1-14.3) higher risk of schizophrenia compared to controls with the COMT-HH genotypes. Future studies with larger sample sizes are, however, needed to confirm this novel finding.

Adult↗
PubMed2003

Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics.

Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds ratio=10.89, 95%CI 1.14-103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics.

Adult↗
PubMed1976

Catechol O-methyltransferase. 7. Affinity labeling with the oxidation products of 6-aminodopamine.

6-Aminodopamine (6-NH2DA) and various analogs of 6-NH2DA have been evaluated for their ability to inactivate purified catechol O-methyltransferase (COMT) in vitro. The inactivation of COMT by these agents could be prevented by including an antioxidant in the preincubation mixture or by excluding oxygen; however, catalase did not protect the enzyme from inactivation. Substrate protection studies and kinetic studies suggested that the loss of enzyme activity resulted from the alkylation of an amino acid residue at the active site of COMT by the quinoid types products which were generated upon air oxidation of 6-NH2DA. In addition, we have explored in more detail the reactivity toward COMT of specific intermediates in the oxidation pathways of 6-NH2DA by using various 6-NH2DA analogs. From the above studies we have concluded that 6-aminodopamine-p-quinone (6-NH2DAQ) is perhaps the most toxic species toward COMT. However, the aminochromes which are formed from 6-NH2DAQ are also effective in inactivating COMT. The results of these studies have provided a useful model system for observing the interaction of 6-NH2DA and its oxidation products with proteins; in addition, it has provided additional insight into the topography of the active site of COMT.

Aerobiosis↗
PubMed2003

Catechol estrogen 4-hydroxyequilenin is a substrate and an inhibitor of catechol-O-methyltransferase.

Redox and/or electrophilic metabolites formed during estrogen metabolism may play a role in estrogen carcinogenesis. 4-Hydroxyequilenin (4-OHEN) is the major phase I catechol metabolite of the equine estrogens equilenin and equilin, which are components of the most widely prescribed estrogen replacement formulation, Premarin. Previously, we have found that 4-OHEN rapidly autoxidized to an o-quinone in vitro and caused toxic effects such as the inactivation of human detoxification enzymes. 4-OHEN has also been shown to be a substrate for catechol-O-methyltransferase (COMT) in human breast cancer cells. In the present study, we demonstrated that 4-OHEN was not only a substrate of recombinant human soluble COMT in vitro with a K(m) of 2.4 microM and k(cat) of 6.0 min(-)(1) but it also inhibited its own methylation by COMT at higher concentrations in the presence of the reducing agent dithiothreitol. In addition, 4-OHEN was found to be an irreversible inhibitor of COMT-catalyzed methylation of the endogenous catechol estrogen 4-hydroxyestradiol with a K(i) of 26.0 microM and a k(2) of 1.62 x 10(-)(2) s(-)(1). 4-OHEN in vitro not only caused the formation of intermolecular disulfide bonds as demonstrated by gel electrophoresis, but electrospray ionization mass spectrometry and matrix-assisted laser desorption ionization time-of-flight mass spectrometry also showed that 4-OHEN alkylated multiple residues of COMT. Peptide mapping experiments further indicated that Cys33 in recombinant human soluble COMT was the residue most likely modified by 4-OHEN in vitro. These data suggest that inhibition of COMT methylation by 4-OHEN might reduce endogenous catechol estrogen clearance in vivo and further enhance toxicity.

Catechol O-Methyltransferase↗
PubMed2003

A structure-activity relationship study of catechol-O-methyltransferase inhibitors combining molecular docking and 3D QSAR methods.

A panel of 92 catechol-O-methyltransferase (COMT) inhibitors was used to examine the molecular interactions affecting their biological activity. COMT inhibitors are used as therapeutic agents in the treatment of Parkinson's disease, but there are limitations in the currently marketed compounds due to adverse side effects. This study combined molecular docking methods with three-dimensional structure-activity relationships (3D QSAR) to analyse possible interactions between COMT and its inhibitors, and to incite the design of new inhibitors. Comparative molecular field analysis (CoMFA) and GRID/GOLPE models were made by using bioactive conformations from docking experiments, which yielded q2 values of 0.594 and 0.636, respectively. The docking results, the COMT X-ray structure, and the 3D QSAR models are in agreement with each other. The models suggest that an interaction between the inhibitor's catechol oxygens and the Mg2+ ion in the COMT active site is important. Both hydrogen bonding with Lys144, Asn170 and Glu199, and hydrophobic contacts with Trp38, Pro174 and Leu198 influence inhibitor binding. Docking suggests that a large R1 substituent of the catechol ring can form hydrophobic contacts with side chains of Val173, Leu198, Met201 and Val203 on the COMT surface. Our models propose that increasing steric volume of e.g. the diethylamine tail of entacapone is favourable for COMT inhibitory activity.

Animals↗
PubMed2005

Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease.

Psychotic symptoms in subjects with Alzheimer disease (AD with psychosis, AD+P) define a phenotype characterized by greater cognitive burden than in AD without psychosis. We have proposed that genes of small effect may contribute to the risk for expression of psychosis in multiple disorders, including AD. Recently, sex-differential association of a three-locus haplotype, including a G-->A transition at codon 108/158 of catechol-O-methyltransferase (COMT) resulting in a Val-->Met substitution, has been reported to confer an increased risk for schizophrenia. The main objective of the study was to determine if COMT genetic variation is associated with risk of psychosis in AD, and included a case-control study of 373 individuals diagnosed with AD with, or without, psychosis. All subjects were characterized for alleles at the three loci associated with schizophrenia, RS737865, COMT G-->A 108/158 (RS4680), and RS165599, and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Both 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. All analyses were stratified by sex. In female subjects, RS4680 demonstrated a modest association with AD+P; RS737865 demonstrated a trend towards an association. There was a highly significant association of AD+P with the four-locus haplotype, which resulted from additive effects of alleles at RS4680 and ERE6 (or RS737865, as this locus was in almost absolute linkage disequilibrium (LD) with ERE6). In male subjects, no single locus test was significant, but there remained a strong association between AD+P and the four-locus haplotype. This association appeared to result from interaction of the ERE6/RS737865, RS4680, and RS165599 loci. Genetic variation in COMT is associated with AD+P, and thus appears to contribute to psychosis risk across disorders. Sex-differential associations of COMT with psychosis may result from variation at, or in LD with, ERE6. Examination of variation at ERE6 in subjects with schizophrenia, and further examination of the independent and additive effects of variations in COMT on gene expression, is warranted.

Aged↗