Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia.
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.
Georgieva
Lyudmila
L
Department of Psychological Medicine, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
Moskvina
Valentina
V
Peirce
Tim
T
Norton
Nadine
N
Bray
Nicholas J
NJ
Jones
Lesley
L
Holmans
Peter
P
Macgregor
Stuart
S
Zammit
Stanley
S
Wilkinson
Jennifer
J
Williams
Hywel
H
Nikolov
Ivan
I
Williams
Nigel
N
Ivanov
Dobril
D
Davis
Kenneth L
KL
Haroutunian
Vahram
V
Buxbaum
Joseph D
JD
Craddock
Nick
N
Kirov
George
G
Owen
Michael J
MJ
O'Donovan
Michael C
MC
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
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