A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain

Bray, Nicholas John ORCID: https://orcid.org/0000-0002-4357-574X, Buckland, Paul Robert, Williams, Nigel Melville ORCID: https://orcid.org/0000-0003-1177-6931, Williams, Hywel John ORCID: https://orcid.org/0000-0001-7758-0312, Norton, Nadine ORCID: https://orcid.org/0000-0002-3848-4288, Owen, Michael John ORCID: https://orcid.org/0000-0003-4798-0862 and O'Donovan, Michael Conlon ORCID: https://orcid.org/0000-0001-7073-2379 2003. A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. The American Journal of Human Genetics 73 (1) , pp. 152-161. 10.1086/376578

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Abstract

The gene encoding catechol-O-methyltransferase (COMT) is a strong candidate for schizophrenia susceptibility, owing to the role of COMT in dopamine metabolism, and the location of the gene within the deleted region in velocardiofacial syndrome, a disorder associated with high rates of schizophrenia. Recently, a highly significant association was reported between schizophrenia and a COMT haplotype in a large case-control sample (Shifman et al. 2002). In addition to a functional valine-->methionine (Val/Met) polymorphism, this haplotype included two noncoding single-nucleotide polymorphisms (SNPs) at either end of the COMT gene. Given the role of COMT in dopamine catabolism and that deletion of 22q11 (containing COMT) is associated with schizophrenia, we postulated that the susceptibility COMT haplotype is associated with low COMT expression. To test this hypothesis, we have applied quantitative measures of allele-specific expression using mRNA from human brain. We demonstrate that COMT is subject to allelic differences in expression in human brain and that the COMT haplotype implicated in schizophrenia (Shifman et al. 2002) is associated with lower expression of COMT mRNA. We also show that the 3' flanking region SNP that gave greatest evidence for association with schizophrenia in that study is transcribed in human brain and exhibits significant differences in allelic expression, with lower relative expression of the associated allele. Our results indicate that COMT variants other than the Val/Met change are of functional importance in human brain and that the haplotype implicated in schizophrenia susceptibility is likely to exert its effect, directly or indirectly, by down-regulating COMT expression.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Subjects:	R Medicine > R Medicine (General)
Publisher:	University of Chicago Press
ISSN:	1537-6605
Last Modified:	01 Dec 2022 09:47
URI:	https://orca.cardiff.ac.uk/id/eprint/558

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