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

Lyudmila Georgieva, Valentina Moskvina, Tim Peirce, Nadine Norton, Nicholas J. Bray, Lesley Jones, Peter Holmans, Stuart MacGregor, Stanley Zammit, Jennifer Wilkinson, Hywel Williams, Ivan Nikolov, Nigel Williams, Dobril Ivanov, Kenneth L. Davis, Vahram Haroutunian, Joseph D. Buxbaum, Nick Craddock, George Kirov, Michael J. OwenMichael C. O'Donovan

Research output: Contribution to journalArticle

87 Scopus citations

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 = ≈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.

Original languageEnglish (US)
Pages (from-to)12469-12474
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number33
DOIs
StatePublished - Aug 15 2006

Keywords

  • Association
  • Oligodentrocyte/myelin-related genes

ASJC Scopus subject areas

  • General

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    Georgieva, L., Moskvina, V., Peirce, T., Norton, N., Bray, N. J., Jones, L., Holmans, P., MacGregor, S., Zammit, S., Wilkinson, J., Williams, H., Nikolov, I., Williams, N., Ivanov, D., Davis, K. L., Haroutunian, V., Buxbaum, J. D., Craddock, N., Kirov, G., ... O'Donovan, M. C. (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, 103(33), 12469-12474. https://doi.org/10.1073/pnas.0603029103