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

Handoko, H. Y.*, Nyholt, D.R., Hayward, N. K., Nertney, D. A., Hannah, D. E., Windus, L. C., McCormack, C. M., Smith, H. J., Filippich, C., James, M. R., & Mowry, B. J. (2005) Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia. Molecular Psychiatry, 10(6), pp. 589-97.

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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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ID Code: 92165
Item Type: Journal Article
Refereed: No
Additional Information: Handoko, H Y Nyholt, D R Hayward, N K Nertney, D A Hannah, D E Windus, L C McCormack, C M Smith, H J Filippich, C James, M R Mowry, B J eng R01 MH 59588/MH/NIMH NIH HHS/ Clinical Trial Controlled Clinical Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. England 2004/10/27 09:00 Mol Psychiatry. 2005 Jun;10(6):589-97.
Keywords: Amino Acid Substitution/genetics, Australia, Catechol O-Methyltransferase/*genetics, Chromosomes, Human, Pair 22/*genetics, European Continental Ancestry Group/genetics, Family, Female, Genetic Predisposition to Disease/genetics, Humans, Linkage Disequilibrium/*genetics, Male, Pedigree, Polymorphism, Single Nucleotide/*genetics, Risk Factors, Schizophrenia/*enzymology/*genetics
DOI: 10.1038/
ISSN: 1359-4184
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2005 Nature Publishing Grou
Deposited On: 21 Jan 2016 04:33
Last Modified: 21 Jan 2016 04:33

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