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Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia

Georgieva, Lyudmila, Escott-Price, Valentina, Peirce, Timothy Rowan, Norton, Nadine, Bray, Nicholas John, Jones, Lesley, Holmans, Peter Alan, Macgregor, Stuart, Zammit, Stanley, Wilkinson, Jennifer Camilla, Williams, Hywel John, Nikolov, Ivan, Williams, Nigel Melville, Ivanov, Dobril, Davis, Kenneth L., Haroutunian, Vahram, Buxbaum, Joseph D., Craddock, Nicholas John, Kirov, George, Owen, Michael John and O'Donovan, Michael Conlon 2006. Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia. Proceedings of the National Academy of Sciences of the United States of America (PNAS) ISSN 1091-6490 103 (33) , pp. 12469-12474. 10.1073/pnas.0603029103

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Abstract

Abnormal oligodendrocyte function has been postulated as a primary etiological event in schizophrenia. Oligodendrocyte lineage transcription factor 2 (OLIG2) encodes a transcription factor central to oligodendrocyte development. Analysis of OLIG2 in a case-control sample (n = approximately 1,400) in the U.K. revealed several SNPs to be associated with schizophrenia (minimum P = 0.0001, gene-wide P = 0.0009). To obtain independent support for this association, we sought evidence for genetic interaction between OLIG2 and three genes of relevance to oligodendrocyte function for which we have reported evidence for association with schizophrenia: CNP, NRG1, and ERBB4. We found interaction effects on disease risk between OLIG2 and CNP (minimum P = 0.0001, corrected P = 0.008) for interaction with ERBB4 (minimum P = 0.002, corrected P = 0.04) but no evidence for interaction with NRG1. To investigate the biological plausibility of the interactions, we sought correlations between the expression of the genes. The results were similar to those of the genetic interaction analysis. OLIG2 expression significantly correlated in cerebral cortex with CNP (P < 10(-7)) and ERBB4 (P = 0.002, corrected P = 0.038) but not NRG1. In mouse striatum, Olig2 and Cnp expression also was correlated, and linkage analysis for trans-effects on gene expression suggests that each locus regulates the other's expression. Our data provide strong convergent evidence that variation in OLIG2 confers susceptibility to schizophrenia alone and as part of a network of genes implicated in oligodendrocyte function.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Publisher: National Academy of Sciences
ISSN: 1091-6490
Date of Acceptance: 26 June 2006
Last Modified: 14 Mar 2018 15:49
URI: http://orca.cf.ac.uk/id/eprint/593

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