Ethnicity-Dependent Effects of Schizophrenia Risk Variants of the OLIG2 Gene on OLIG2 Transcription and White Matter Integrity

Abstract

Previous studies have indicated associations between several OLIG2 gene single-nucleotide polymorphisms (SNPs) and susceptibility to schizophrenia among Caucasians. Consistent with these findings, postmortem brain and diffusion tensor imaging studies have indicated that the schizophrenia-risk-associated allele (A) in the OLIG2 SNP rs1059004 predicts lower OLIG2 gene expression in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients and reduced white matter (WM) integrity of the corona radiata in normal brains among Caucasians. In an effort to replicate the association between this variant and WM integrity among healthy Japanese, we found that the number of A alleles was positively correlated with WM integrity in some fiber tracts, including the right posterior limb of the internal capsule, and with mean blood flow in a widespread area, including the inferior frontal operculum, orbital area, and triangular gyrus. Because the A allele affected WM integrity in opposite directions in Japanese and Caucasians, we investigated a possible association between the OLIG2 gene SNPs and the expression level of OLIG2 transcripts in postmortem DLPFCs. We evaluated rs1059004 and additional SNPs in the 5' upstream and 3' downstream regions of rs1059004 to cover the broader region of the OLIG2 gene. The 2 SNPs (rs1059004 and rs9653711) had opposite effects on OLIG2 gene expression in the DLPFC in Japanese and Caucasians. These findings suggest ethnicity-dependent opposite effects of OLIG2 gene SNPs on WM integrity and OLIG2 gene expression in the brain, which may partially explain the failures in replicating associations between genetic variants and psychiatric phenotypes among ethnicities.

Keywords: OLIG2 polymorphism; schizophrenia; white matter integrity/cerebral blood flow/OLIG2 gene expression/ethnic difference.

Fig. 1.

Impact of OLIG2 gene polymorphisms on cognitive function in healthy subjects and patients with schizophrenia. (a) In the SNP rs1005573, 2-way ANOVA indicated that the main effect of genotype was also significant for the digit span, arithmetic, and block design subtests of the WAIS-III (P = .047, P = .028, and P = .031, respectively). Post hoc analysis showed that the subjects with the TT genotype (TT) showed significantly lower scores on the digit span subtest than did the subjects with the CT genotype (CT) (Bonferroni corrected, †P = .018). In each genotype group for rs1005573, there were significantly lower scores on the digit span, arithmetic, and block design subtests in patients with schizophrenia than in healthy controls (Bonferroni corrected, ***P < .001). (b) In the SNP rs1005573, 2-way ANOVA revealed significant genotype-by-diagnosis interactions for the vocabulary and letter-number sequencing subtests (respectively, P = .044and P = .028). In each genotype group for rs1005573, patients with schizophrenia had significantly lower scores on the both subtest than did healthy controls (Bonferroni corrected, ***P < .001 or **P < .01

Fig. 2.

Brain regions showing significant associations of the OLIG2 gene polymorphism rs1059004 with fractional anisotropy and regional cerebral blood flow. (a) The white matter region where the positive association between the fractional anisotropy and number of A alleles of the OLIG2 gene polymorphism rs1059004 was observed based on threshold-free cluster enhancement, with the significance level set at P < .05 (corrected for familywise error rate based on 5000 permutations), is shown in yellow-orange. The associated region is overlaid on a single-subject T1 SPM8 image. Significantly associated white matter was widespread in the right posterior limb of the internal capsule, the right retrolenticular part of the internal capsule, and the right external capsule. The anatomical labels and significant clusters of major white matter fibers were determined using the ICBM DTI-81 Atlas (http://www.bmap.ucla.edu/portfolio/atlases/ICBM_DTI-81_Atlas/). (b) The white matter region where the positive association between the fractional anisotropy and the number of A alleles of the OLIG2 SNP rs1059004 was observed, with the significance level set at P < .05 (uncorrected for multiple comparisons), is shown in yellow-orange. The associated region was overlaid on a single-subject T1 SPM8 image. Significantly associated white matter was widespread in the bilateral posterior limb of the internal capsule, the bilateral retrolenticular part of the internal capsule, and the bilateral external capsule. (c) Brain regions marked in red indicate the target areas of the brain analyzed with arterial spin labeling analyses. (d) The brain region where the positive association between the mean resting cerebral blood flow and the number of A alleles of the OLIG2 gene polymorphism rs1059004 was observed based on threshold-free cluster enhancement, with the significance level set at P < .05 (corrected for familywise error rate based on 5000 permutations), is shown in yellow-orange. The associated region is overlaid on a single-subject T1 SPM8 image. Significantly associated brain regions included the precuneus, middle and posterior cingulate cortices, putamen, insula, and globus pallidus.

Fig. 3.

Impact of the OLIG2 gene SNPs on OLIG2 gene expression among Caucasian and Japanese postmortem DLPFC specimens. (a) Carriers of the A allele of the SNP rs100594 showed significantly lower OLIG2 gene expression in the postmortem DLPFC than CC carriers among Caucasians (*P = .045). In the OLIG2 gene SNP rs9653711, C allele carriers had significantly decreased OLIG2 gene expression compared with GG carriers among Caucasians (*P = .035). (b) In contrast, among the Japanese population, carriers of the A allele of the SNP rs100594 showed higher OLIG2 gene expression in the postmortem DLPFC than CC carriers, although the difference did not reach statistical significance (P = .055). As the SNP rs9653711 is in perfect LD with rs1059004, the results of OLIG2 gene expression analysis of rs9653711 were consistent with the results of rs1059004.