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

Handoko, H. Y. and Nyholt, D. R. and Hayward, N. K. and Nertney, D. A. and Hannah, D. E. and Windus, L. C. ORCID: and McCormack, C. M. and Smith, H. J. and Flippich, C. and James, M. R. and Mowry, B. J. (2004) Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia. Molecular Psychiatry, 10 (6). pp. 589-597. ISSN 1359-4184


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 ∼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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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Faculty/School / Institute/Centre: No Faculty
Faculty/School / Institute/Centre: No Faculty
Date Deposited: 27 Oct 2020 04:30
Last Modified: 27 Oct 2020 05:29
Uncontrolled Keywords: COMT; schizophrenia; chromosome 22; single-nucleotide polymorphism; dopamine; complex disorder
Fields of Research (2008): 06 Biological Sciences > 0604 Genetics > 060412 Quantitative Genetics (incl. Disease and Trait Mapping Genetics)
Fields of Research (2020): 31 BIOLOGICAL SCIENCES > 3105 Genetics > 310506 Gene mapping
Socio-Economic Objectives (2008): E Expanding Knowledge > 97 Expanding Knowledge > 970106 Expanding Knowledge in the Biological Sciences
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