title: Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia.
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.
authors.affiliation: Department of Psychological Medicine, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Georgieva
authors.forename: Valentina
authors.initials: V
authors.lastname: Moskvina
authors.forename: Tim
authors.initials: T
authors.lastname: Peirce
authors.forename: Nadine
authors.initials: N
authors.lastname: Norton
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bray
authors.forename: Lesley
authors.initials: L
authors.lastname: Jones
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.forename: Stuart
authors.initials: S
authors.lastname: Macgregor
authors.forename: Stanley
authors.initials: S
authors.lastname: Zammit
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wilkinson
authors.forename: Hywel
authors.initials: H
authors.lastname: Williams
authors.forename: Ivan
authors.initials: I
authors.lastname: Nikolov
authors.forename: Nigel
authors.initials: N
authors.lastname: Williams
authors.forename: Dobril
authors.initials: D
authors.lastname: Ivanov
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Davis
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Nick
authors.initials: N
authors.lastname: Craddock
authors.forename: George
authors.initials: G
authors.lastname: Kirov
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000235:genetics; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D016022:Case-Control Studies; D066246:ErbB Receptors / Q000235:genetics; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020890:Neuregulin-1; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D066247:Receptor, ErbB-4; D012559:Schizophrenia / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology; D013223:Statistics as Topic
chemical_list: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D000076104:Oligodendrocyte Transcription Factor 2; D066247:Receptor, ErbB-4; C094131:NRG1 protein, human; C405708:OLIG2 protein, human; C512773:Olig2 protein, mouse; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse