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A highly significant association between a COMT haplotype and schizophrenia.

ABSTRACT: Several lines of evidence have placed the catechol-O-methyltransferase (COMT) gene in the limelight as a candidate gene for schizophrenia. One of these is its biochemical function in metabolism of catecholamine neurotransmitters; another is the microdeletion, on chromosome 22q11, that includes the COMT gene and causes velocardiofacial syndrome, a syndrome associated with a high rate of psychosis, particularly schizophrenia. The interest in the COMT gene as a candidate risk factor for schizophrenia has led to numerous linkage and association analyses. These, however, have failed to produce any conclusive result. Here we report an efficient approach to gene discovery. The approach consists of (i) a large sample size-to our knowledge, the present study is the largest case-control study performed to date in schizophrenia; (ii) the use of Ashkenazi Jews, a well defined homogeneous population; and (iii) a stepwise procedure in which several single nucleotide polymorphisms (SNPs) are scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. We found a highly significant association between schizophrenia and a COMT haplotype (P=9.5x10-8). The approach presented can be widely implemented for the genetic dissection of other common diseases.

SUBMITTER: Shifman S

PROVIDER: S-EPMC378567 | biostudies-literature | 2002 Dec

REPOSITORIES: biostudies-literature

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A highly significant association between a COMT haplotype and schizophrenia.

Shifman Sagiv S Bronstein Michal M Sternfeld Meira M Pisanté-Shalom Anne A Lev-Lehman Efrat E Weizman Avraham A Reznik Ilya I Spivak Baruch B Grisaru Nimrod N Karp Leon L Schiffer Richard R Kotler Moshe M Strous Rael D RD Swartz-Vanetik Marnina M Knobler Haim Y HY Shinar Eilat E Beckmann Jacques S JS Yakir Benjamin B Risch Neil N Zak Naomi B NB Darvasi Ariel A

American journal of human genetics 20021025 6

Several lines of evidence have placed the catechol-O-methyltransferase (COMT) gene in the limelight as a candidate gene for schizophrenia. One of these is its biochemical function in metabolism of catecholamine neurotransmitters; another is the microdeletion, on chromosome 22q11, that includes the COMT gene and causes velocardiofacial syndrome, a syndrome associated with a high rate of psychosis, particularly schizophrenia. The interest in the COMT gene as a candidate risk factor for schizophren ...[more]

PMID: 12402217

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Project description:Catechol-O-methyl transferase (COMT) is a catabolic enzyme involved in the degradation of a number of bioactive molecules; of principal interest to psychiatry, these include dopamine. The enzyme is encoded by the COMT gene. COMT is located (along with 47 other genes) in a fragment of chromosome 22q11 which when deleted results in a complex syndrome, the psychiatric manifestations of which include schizophrenia and other psychoses. These 2 observations have placed COMT near the top of a rather long list of plausible candidate genes for schizophrenia. The ability to test the hypothesis that COMT might be a susceptibility gene for schizophrenia has been simplified in principle by the existence of a valine-to-methionine (Val/Met) polymorphism which results respectively in high and low activity forms of the enzyme. Given the unequivocal effect of this polymorphism on the function of COMT, and the evidence for a critical role for dopamine in the pathophysiology and treatment of psychosis, there are strong prior expectations that Val/Met influences susceptibility to schizophrenia as well as other psychiatric phenotypes. Indeed the Val/Met polymorphism has become the most widely studied polymorphism in psychiatry. In this review, we consider the evidence for and against the involvement of COMT in schizophrenia. The current data allow us to virtually exclude a simple relationship between schizophrenia and the Val/Met variant previously thought to dominate COMT function. However, recent data suggest a more complex pattern of genetic regulation of COMT function beyond that attributable to the Val/Met locus. Moreover, it is also clear that there is a complex nonlinear relationship between dopamine availability and brain function. These 2 factors, allied to phenotypic complexity within schizophrenia, make it difficult to draw strong conclusions regarding COMT in schizophrenia. Nevertheless, emerging research that takes greater account of all these levels of complexity is beginning to provide tantalizing, but far from definitive, support for the view that COMT influences susceptibility to at least some forms of psychosis.

Project description:Background:COMT gene polymorphism is associated with mental disorders and sensitivity to pain. In this study, we investigated the association between the COMT gene polymorphism and labor anxiety and analgesia in pregnant women. Subjects and methods:A total of 425 pregnant women undergoing labor analgesia were selected from May 2016 to February 2018. The COMT gene polymorphism was detected through the PCR with restriction fragment length polymorphism technique before childbirth. According to a COMT genotype, the enrolled pregnant women were subdivided into the Val/Val (allele GG) group, the Met/Met (allele AA) group, and the Val/Met (allele GA) group. Then, the intervertebral space of all pregnant women was injected with 3 mL of 2% lidocaine +6 mL of 0.08% ropivacaine and 6 µg of fentanyl. Labor analgesia was administered as follows: 80 mg of 0.08% ropivacaine +100 µg of fentanyl + normal saline to 100 mL. The general characteristics of the women were examined and recorded. In addition, the State Anxiety Inventory (SAI), VAS, Ramsay sedation score, and epinephrine and norepinephrine levels were compared and analyzed. Results:A total of 391 pregnant women were enrolled in this study; among these pregnant women, there were 180 pregnant women in the GG group, 132 in the GA group, and 99 in the AA group. The minor allele frequency of COMT polymorphism among these pregnant women was 32.8%. Compared with the GG group, the SAI and VAS scores were higher, the Ramsay sedation score was lower, and the epinephrine and norepinephrine levels were higher in AA and GA groups (P<0.05). Nonetheless, there was no statistically significant difference in the SAI, VAS, Ramsay sedation score, and epinephrine and norepinephrine levels between the groups AA and GA (P>0.05). Conclusion:The COMT gene polymorphism was associated with labor anxiety and analgesia among pregnant women, and the Val158Met mutation in the COMT gene could lead to worse labor anxiety and less-effective labor analgesia in pregnant women.

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A highly significant association between a COMT haplotype and schizophrenia.

Publications

A highly significant association between a COMT haplotype and schizophrenia.

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