TY - JOUR
T1 - Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia
AU - Georgieva, Lyudmila
AU - Moskvina, Valentina
AU - Peirce, Tim
AU - Norton, Nadine
AU - Bray, Nicholas J.
AU - Jones, Lesley
AU - Holmans, Peter
AU - MacGregor, Stuart
AU - Zammit, Stanley
AU - Wilkinson, Jennifer
AU - Williams, Hywel
AU - Nikolov, Ivan
AU - Williams, Nigel
AU - Ivanov, Dobril
AU - Davis, Kenneth L.
AU - Haroutunian, Vahram
AU - Buxbaum, Joseph D.
AU - Craddock, Nick
AU - Kirov, George
AU - Owen, Michael J.
AU - O'Donovan, Michael C.
PY - 2006/8/15
Y1 - 2006/8/15
N2 - 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.
AB - 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.
KW - Association
KW - Oligodentrocyte/myelin-related genes
UR - http://www.scopus.com/inward/record.url?scp=33747597585&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33747597585&partnerID=8YFLogxK
U2 - 10.1073/pnas.0603029103
DO - 10.1073/pnas.0603029103
M3 - Article
C2 - 16891421
AN - SCOPUS:33747597585
SN - 0027-8424
VL - 103
SP - 12469
EP - 12474
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 33
ER -