Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia

Queensland Centre for Mental Health Research, The Park, Centre for Mental Health, Wacol, QLD, Australia.
Molecular Psychiatry (Impact Factor: 14.5). 07/2005; 10(6):589-97. DOI: 10.1038/
Source: PubMed


Several lines of evidence have implicated the catechol-O-methyltransferase (COMT) gene as a candidate for schizophrenia (SZ) susceptibility, not only because it encodes a key dopamine catabolic enzyme but also because it maps to the velocardiofacial syndrome region of chromosome 22q11 which has long been associated with SZ predisposition. The interest in COMT as a candidate SZ risk factor has led to numerous case-control and family-based studies, with the majority placing emphasis on examining a functional Val/Met polymorphism within this enzyme. Unfortunately, these studies have continually produced conflicting results. To assess the genetic contribution of other COMT variants to SZ susceptibility, we investigated three single-nucleotide polymorphisms (SNPs) (rs737865, rs4633, rs165599) in addition to the Val/Met variant (rs4680) in a highly selected sample of Australian Caucasian families containing 107 patients with SZ. The Val/Met and rs4633 variants showed nominally significant associations with SZ (P<0.05), although neither of the individual SNPs remained significant after adjusting for multiple testing (most significant P=0.1174). However, haplotype analyses showed strong evidence of an association; the most significant being the three-marker haplotype rs737865-rs4680-rs165599 (global P=0.0022), which spans more than 26 kb. Importantly, conditional analyses indicated the presence of two separate and interacting effects within this haplotype, irrespective of gender. In addition, our results indicate the Val/Met polymorphism is not disease-causing and is simply in strong linkage disequilibrium with a causative effect, which interacts with another as yet unidentified variant approximately 20 kb away. These results may help explain the inconsistent results reported on the Val/Met polymorphism and have important implications for future investigations into the role of COMT in SZ susceptibility.

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    • "However, current data on other variants of the COMT gene could also be relevant [Shield et al., 2004; Molero et al., 2007]. Several other SNPs that were tested for an association with schizophrenia have shown conflicting results [Chen et al., 2004; Handoko et al., 2005]. A recent study analyzing 14 polymorphisms in a case-control study of 876 Han Chinese found that none of these polymorphisms contributed Grant sponsor: Stanley Medical Research Institute; Grant numbers: 03T- 459, 05T-726; Grant sponsor: Department of Veterans Affairs, VISN 16; Grant sponsor: Mental Illness Research, Education and Clinical Center (MIRECC); Grant numbers: K05-DA0454, P50-DA18827, U01-MH79639; Grant sponsor: United States National Institute of Health; Grant numbers: K05-DA0454, P50-DA18827, U01-MH79639. "
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    ABSTRACT: The gene encoding Catechol-O-methyltransferase (COMT), a dopamine catabolic enzyme, has been associated inconsistently with schizophrenia in spite of consistent evidence for dopaminergic dysfunction in the prefrontal cortex (PFC) of schizophrenia. Since one contribution to this inconsistency might be genetic heterogeneity, this study investigated whether the COMT gene was associated with the development and symptoms of schizophrenia in relatively genetically homogeneous Chinese schizophrenic patients. We analyzed two polymorphisms (rs740603 and rs4818) of the COMT gene in a case-control study of 604 Han Chinese (284 patients and 320 controls). The patients' psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). We found no significant differences in the rs740603 and rs4818 genotype and allele distributions between the patient and control groups. Quantitative trait analysis by the UNPHASED program showed that the rs740603 and rs740603(G)-rs4818(G) haplotypes were associated with negative symptoms in the schizophrenic patients, particularly among female patients. Thus, the COMT gene polymorphisms may not contribute to the susceptibility to schizophrenia, but may contribute to the negative symptoms of schizophrenia among Han Chinese.
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    • "A large Ashkenazi sample showed highly significant association for two other polymorphisms (in intron 1, rs737865, and 3′ UTR (rs165599), as well as for a core haplotype of three markers including val (P=9.5 × 10 -8 ) (Reenila and Mannisto, 2001). Handoko et al, in a recent analysis of these SNPs and this three-marker haplotype (rs737865-rs4680- rs165599), found that while none of the individual SNPs showed significant association (when corrected for multiple comparisons), the haplotype showed significant evidence of association (Handoko et al., 2005). Nicodemus et al (2007) (Nicodemus et al., 2007) recently reported that diplotypes comprised of haplotypes shown to be most deleterious in terms of prefrontal function in our earlier fMRI analysis (Meyer-Lindenberg et al., 2006) were significantly enriched in a case control sample of patients with schizophrenia that was negative for any of the individual SNPs in the haplotype. "
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    ABSTRACT: Functional variants in the catechol-O-methyltransferase (COMT) gene have been shown to impact cognitive function, cortical physiology and risk for schizophrenia. A recent study showed that previously reported effects of the functional val158met SNP (rs4680) on brain function are modified by other functional SNPs and haplotypes in the gene, though it was unknown if these effects are also seen in brain structure. We used voxel-based morphometry to investigate the impact of multiple functional variants in COMT on gray matter volume in a large group of 151 healthy volunteers from the CBDB/NIMH Genetic Study of Schizophrenia. We found that the previously described rs4680 val risk variant affects hippocampal and dorsolateral prefrontal (DLPFC) gray matter volume. In addition, we found that this SNP interacts with a variant in the P2 promoter region (rs2097603) in predicting changes in hippocampal gray matter volume consistent with a nonlinear effect of extracellular dopamine. We report evidence that interacting functional variants in COMT affect gray matter regional volume in hippocampus and DLPFC, providing further in vivo validation of the biological impact of complex genetic variation in COMT on neural systems relevant for the pathophysiology of schizophrenia and extending observations of nonlinear dependence of prefrontal neurons on extracellular dopamine to the domain of human brain structure.
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    • "These calculations provide a baseline indication of power as our study design includes many families with multiple affected sibs and/or unaffected sibs plus which should result in increased power [Martin et al., 2000] and 26% of families have both parents genotyped (Table I). Three COMT SNPs rs737865, rs4680, and rs165599 were genotyped by primer extension reaction and MALDI-TOF mass spectrometry (MassARRAY, Sequenom, Inc., San Diego, CA) as described elsewhere [Handoko et al., 2005]. "
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    ABSTRACT: The Val158Met polymorphism of the gene encoding catechol-O-methyltransferase (COMT) is one of the most widely tested variants for association with psychiatric disorders, but replication has been inconsistent including both sex limitation and heterogeneity of the associated allele. In this study we investigate the association between three SNPs from COMT and anxiety and depression disorders and neuroticism all measured within the same study sample. Participants were selected as sibling pairs (or multiples) that were either concordant or discordant for extreme neuroticism scores from a total sample of 18,742 Australian twin individuals and their siblings. All participants completed the Composite International Diagnostic Interview (CIDI) from which diagnoses of DSM-IV depression and anxiety disorders were determined. Of the participants, 674 had a diagnosis of anxiety and/or depression from 492 families. Study participants (n = 2,045 from 987 families) plus, where possible, their parents were genotyped for rs737865, rs4680 (Val158Met), and rs165599. Using family based tests we looked for association between these variants and neuroticism, depression, anxiety, panic disorder and agarophobia (PDAG) and obsessive compulsive disorder. We found no convincing evidence for association either in allelic or genotypic tests for the total sample or when the sample was stratified by sex. Haplotype T-G-G showed weak association (P = 0.042) with PDAG before correction for multiple testing; association between this haplotype and schizophrenia has been previously reported in an Australian sample.
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