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

Article


Handoko, HY, Nyholt, DR, Hayward, NK, Nertney, DA, Hannah, DE, Windus, LC, McCormack, CM, Smith, HJ, Flippich, C, James, MR and Mowry, BJ. 2004. "Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia." Molecular Psychiatry. 10 (6), pp. 589-597. https://doi.org/10.1038/sj.mp.4001606
Article Title

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

ERA Journal ID13102
Article CategoryArticle
AuthorsHandoko, HY (Author), Nyholt, DR (Author), Hayward, NK (Author), Nertney, DA (Author), Hannah, DE (Author), Windus, LC (Author), McCormack, CM (Author), Smith, HJ (Author), Flippich, C (Author), James, MR (Author) and Mowry, BJ (Author)
Journal TitleMolecular Psychiatry
Journal Citation10 (6), pp. 589-597
Number of Pages9
Year2004
Place of PublicationUnited Kingdom
ISSN1359-4184
1476-5578
Digital Object Identifier (DOI)https://doi.org/10.1038/sj.mp.4001606
Web Address (URL)https://www.nature.com/articles/4001606
Abstract

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.

KeywordsCOMT; schizophrenia; chromosome 22; single-nucleotide polymorphism; dopamine; complex disorder
ANZSRC Field of Research 2020310506. Gene mapping
Open access urlhttps://www.nature.com/articles/4001606
Institution of OriginUniversity of Southern Queensland
Byline AffiliationsDepartment of Health, Queensland
Queensland Institute of Medical Research, Australia
University of Queensland
Queensland Centre for Mental Health Research, Australia
Funding source
NHMRC
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