Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: A large-scale association study plus meta-analysis

Fan, Jinbo; Zhang, Chang Shun; Gu, Ning; Li, Xing Wang; Sun, Wei; Wang, Hong Yan; Feng, Guo; Clair, David St; He, Lin

doi:10.1016/j.biopsych.2004.10.018

Cited by 228 publications

(133 citation statements)

References 52 publications

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“…Disruption in dopamine function could contribute to both the motor deficits as well as the Schizophrenic like behaviors associated with Batten disease. Indeed, polymorphisms within COMT have been reported to decrease the levels of enzyme within the brain (Weinshilboum and Raymond, 1977;Boudikova et al, 1990) and have been associated with Schizophrenia, motor impairments, and cognitive decline, (Fan et al, 2005;Galderisi et al, 2005;Horowitz et al, 2005). As JNCL progresses, hallucinations and Schizophrenic-like behavior becomes common.…”

Section: Discussionmentioning

confidence: 99%

Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of juvenile neuronal ceroid lipofuscinosis

et al. 2007

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Batten disease, or juvenile neuronal ceroid lipofuscinosis (JNCL), results from mutations in the CLN3 gene. This disorder presents clinically around the age of five years with visual deficits progressing to include seizures, cognitive impairment, motor deterioration, hallucinations, and premature death by the third to forth decade of life. The motor deficits include coordination and gait abnormalities, myoclonic jerks, inability to initiate movements, and spasticity. Previous work from our laboratory has identified an early reduction in catechol-O-methyltransferase (COMT), an enzyme responsible for the efficient degradation of dopamine. Alterations in the kinetics of dopamine metabolism could cause the accumulation of undegraded or unsequestered dopamine leading to the formation of toxic dopamine intermediates. We report an imbalance in the catabolism of dopamine in three month Cln3 -/-mice persisting through nine months of age that may be causal to oxidative damage within the striatum at nine months of age. Combined with the Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript previously reported inflammatory changes and loss of post-synaptic D1α receptors, this could facilitate cell loss in striatal projection regions and underlie a general locomotion deficit that becomes apparent at twelve months of age in Cln3 -/-mice. This study provides evidence for early changes in the kinetics of COMT in the Cln3 -/-mouse striatum, affecting the turnover of dopamine, likely leading to neuron loss and motor deficits. These data provide novel insights into the basis of motor deficits in JNCL and how alterations in dopamine catabolism may result in oxidative damage and localized neuronal loss in this disorder.

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Section: Discussionmentioning

confidence: 99%

Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of juvenile neuronal ceroid lipofuscinosis

et al. 2007

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“…Nevertheless, two other studies did not report a significant contribution of the Val 158 Met polymorphism of the COMT gene to schizophrenia and concluded that either the Val allele is in linkage disequilibrium (LD) with a nearby causal marker or the results differ when ethnically different populations are considered or the risk conferred by the Val allele is extremely low. 12,13 Results have also been obtained that suggest an eventual influence of this polymorphism in the response of schizophrenic patients to typical 14 and atypical 15 neuroleptics.…”

Section: Introductionmentioning

confidence: 90%

Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment

et al. 2007

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Genetic variation in the catechol-O-methyltransferase (COMT) gene may influence the susceptibility to schizophrenia and the response to neuroleptic treatment. The authors tested for an association between a COMT haplotype and schizophrenia-spectrum disorders and for an eventual influence of a specific COMT genotype in the clinical outcome and in the response to treatment. The genotypes for single nucleotide polymorphisms rs737865, rs4633, rs6267, rs4680 (Val 158 Met) and rs165599 were determined in 207 patients with schizophrenia-spectrum disorders and 204 paired controls. Statistical tests for linkage disequilibrium and for case-control differences in haplotype frequencies were performed using log-linear modelling embedded within the expectation-maximization algorithm. P-values based on permutations were calculated using the software UNPHASED, and odds ratios were estimated using the SHEsis platform. The response to neuroleptic treatment was assessed by the Global Assessment of Functioning scale and the severity of psychotic symptoms by the positive and negative syndrome scale (PANSS) scale. The overall disease status was significantly associated with the T-G (Val) diplotype for rs4633-rs4680 (P ¼ 0.0049). A significant association was observed between schizophrenia, but not other related disorders, and genotypes GG (Val/Val) for rs4680 and TT for rs4633. Val/Val patients with schizophrenia showed a higher severity of the psychotic symptoms and a worse response to the neuroleptic treatment. COMT genetic variation seems to be involved in the psychotic symptomatology of the schizophreniaspectrum disorders and specifically in the narrow schizophrenia phenotype. Our results show an influence of the Val 158 Met polymorphism on the severity of psychotic symptoms and on the response to treatment.

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“…Estimated allele frequencies were similar to previously reported results in Caucasians (Table 2). 11,16,17,20,29 Age, gender and task performance were balanced between genotype groups (Supplementary Table). With one exception, pairwise LD was significant and extensive, but not complete, underscoring the uncertainty of haplotype information (Table 3).…”

Section: Geneticsmentioning

confidence: 99%

“…9 A common val 108/158 met substitution affects the stability of the protein and leads to a significant decrease in the activity of the enzyme in brain and lymphocytes. 10 Several studies have demonstrated that this coding variant impacts on indices of PFC function, including PFC activation during working memory, 11 PFC-dependent neuropsychological performance, 12 response to amphetamine in healthy humans, 13 and prefrontal regulation of midbrain dopamine synthesis 14,15 However, despite the consistent findings implicating the COMT val 108/158 met polymorphism in prefrontal function, the evidence supporting association of this coding variant with schizophrenia is inconclusive 16,17 and the isolated association of this polymorphism with the schizophrenia phenotype is likely to be small. One reason contributing to this apparent discrepancy is that additonal genetic variability in COMT may be important.…”

Section: Introductionmentioning

confidence: 99%

Impact of complex genetic variation in COMT on human brain function

et al. 2006

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Catechol-O-methyltransferase (COMT) has been shown to be critical for prefrontal dopamine flux, prefrontal cortex-dependent cognition and activation. Several potentially functional variants in the gene have been identified, but considerable controversy exists regarding the contribution of individual alleles and haplotypes to risk for schizophrenia, partly because clinical phenotypes are ill-defined and preclinical studies are limited by lack of adequate models. Here, we propose a neuroimaging approach to overcome these limitations by characterizing the functional impact of ambiguous haplotypes on a neural system-level intermediate phenotype in humans. Studying 126 healthy control subjects during a workingmemory paradigm, we find that a previously described risk variant in a functional Val158Met (rs4680) polymorphism interacts with a P2 promoter region SNP (rs2097603) and an SNP in the 3 0 region (rs165599) in predicting inefficient prefrontal working memory response. We report evidence that the nonlinear response of prefrontal neurons to dopaminergic stimulation is a neural mechanism underlying these nonadditive genetic effects. This work provides an in vivo approach to functional validation in brain of the biological impact of complex genetic variations within a gene that may be critical for its clinical association.

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Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: A large-scale association study plus meta-analysis

Cited by 228 publications

References 52 publications

Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of juvenile neuronal ceroid lipofuscinosis

Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of juvenile neuronal ceroid lipofuscinosis

Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment

Impact of complex genetic variation in COMT on human brain function

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