4 August 2006. Reduced expression of genes involved with myelination and myelinating oligodendrocytes is a widely observed phenomenon in schizophrenia. Imaging and morphological studies also point to problems with myelination and oligodendrocytes in the disease. By homing in on genes involved in this process, Michael O’Donovan, Mike Owen, and colleagues at Cardiff University in the United Kingdom and in New York have identified a new potential susceptibility gene for schizophrenia. The gene, OLIG2 (oligodendrocyte lineage transcription factor 2), is a master regulator of oligodendrocyte differentiation and function. SNP association studies suggest that OLIG2 alleles confer risk for schizophrenia by themselves, as well as in interaction with other myelin-related genes. Evidence for a functional relationship between the interacting genes involved in oligodendrocyte function was also found from gene expression studies suggesting coordinated expression. The study is set to appear in PNAS online today.
Several oligodendrocyte/myelination-related genes have previously been implicated in schizophrenia. Recently, the Cardiff group showed that a low-expressing allele of the mature oligodendrocyte marker CNP (2’3’-cyclic nucleotide 3’phosphodiesterase) gene is linked to schizophrenia (see SRF related news story). But the lower expression of CNP and several other genes observed in schizophrenia could be a downstream effect of other genetic variations or environmental factors. In the current report, first author Lyudmila Georgieva and colleagues selected the OLIG2 transcription factor as a candidate gene which could affect the expression of many other oligodendrocyte genes. They applied several independent methods to ask whether OLIG2 variants influence susceptibility to schizophrenia.
In the first analysis, the researchers genotyped nine known markers across the OLIG2 gene in pooled DNA from cases and controls and then in individuals, resulting in two SNPs that were significantly linked to disease. A second analysis screened DNA from people with schizophrenia for new polymorphisms, and revealed additional associated SNPs. Individual genotyping of between 600 and 700 cases and controls yielded three SNPs that were strongly associated with disease.
If altered oligodendrocyte function or myelination were critical to the risk of schizophrenia, the researchers reasoned, they might see interactions between OLIG2 and CNP variants, and that is exactly what they observed. They also tested for interaction with two other risk genes, those for neuregulin-1 (NRG1) and its receptor ErbB4. While no interaction was detected for NRG1 and OLIG2, there was a significant interaction with ErbB4, although it was not as strong as that seen for CNP.
To take another measure of functional links between the oligodendrocyte genes, the researchers looked for coexpression of mRNAs in brain tissue. There, the expression data correlations followed their genetic data precisely. From gene chip experiments, they found a strong positive correlation of OLIG2 and CNP expression in several brain regions. One of two probes for ErbB4 message showed a negative correlation with OLIG2 expression, but there was no correlation of OLIG2 with NRG1. Using mouse brain tissue, they found evidence of linkage between OLIG2 expression and the CNP locus, and vice versa, suggesting that the genes may be mutually regulating each other.
“The data presented here provide a coherent and strong statistical case for the hypothesis that OLIG2 is a susceptibility gene for schizophrenia, but the mechanistic influences to be drawn are yet unclear,” the authors write. Also unclear is the identity of the functional allele or alleles of OLIG2 that confer the main risk and the interaction with CNP. But by their approach of combining multiple analyses, the authors put the legs under a sturdy platform to support their stated hypothesis that OLIG2 is an important “host gene” for variants that affect schizophrenia risk by affecting a whole network of oligodendrocyte/myelin-associated genes.—Pat McCaffrey.
Georgieva L, Moskvina V, Peirce T, Norton N, Bray NJ, Jones L, Holmans P, MacGregor S, Zammit S, Wilkinson J, Williams H, Nikolov I, Williams N, Ivanov D, Davis KL, Haroutunian V, Buxbaum JD, Craddock N, Kirov G, Owen MJ, O’Donovan MC. Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia. Proc Natl Acad Sci U S A. 2006 Aug 4; [Epub ahead of print] Abstract