ASSOCIATION BETWEEN GENETIC POLYMORPHISMS OF WNT SIGNALING GENES AND SCHIZOPHRENIA IN A KOREAN POPULATION

Abstract Background The disruption of the Wnt/β-catenin pathway has been involved in the pathogenesis of schizophrenia, dysregulating of brain development. R-spondin 2 (Rspo2), encoded by the RSPO2 gene, is a secreted ligand enhancing Wnt signaling, and activating β-catenin synergistically with Wnt. Aims & Objectives In this study, some functional SNPs of Wnt signaling genes were examined about the genetic association of schizophrenia. We investigated the involvement of RSPO2 in schizophrenia through analysis of associations between single nucleotide polymorphisms (SNPs) of RSPO2 and schizophrenia. Method MK-801-treated schizophrenic mice have been made to measure the mRNA expression of Wnt signaling genes in the brain. Pre-pulse inhibition test (PPI) was performed to measure the sensorimotor gating difference of the schizophrenia model. We selected 6 genes and SNPs associated with the Wnt signaling at the National Center for Biotechnology Information SNP database. On RSPO2, 5 SNPs [rs555008 (A/C), rs601558 (G/A), rs9297407 (A/G), rs423940 (C/T), rs374810 (G/A)] were genotyped in 161 patients with schizophrenia and 455 control subjects. A genetic association between SNPs and schizophrenia was analyzed using logistic regression analysis with multiple inheritance models. We also detected the RSPO2 promoter activity using luciferase activity assay. Results Two SNPs (rs374810, rs423940) of the RSPO2 and one SNP (rs1261085) of TCF4 showed a different genotype frequency between the schizophrenia patients and the controls. We found that rs374810, which was located on the promoter region of RSPO2, was significantly associated with schizophrenia in the additive [odds ratio (OR) = 1.45, 95% confidential interval (CI) = 1.11-1.89, p = 0.0055], dominant (OR = 1.62, 95% CI = 1.04-2.52, p = 0.029) and recessive models (OR = 1.66, 95% CI = 1.09-2.52, p = 0.018). In these models, the frequency of the TT genotype was increased in patients with schizophrenia (0.30), compared to control subjects (0.21). In the haplotype analysis on SNPs of RSPO2, the AAATA haplotype showed a significant association with schizophrenia (OR = 1.72, 95% CI = 1.16-2.55, p = 0.0075). In addition, we assessed the promoter activity according to the alleles of rs374810 using the luciferase reporter system. The T allele of rs374810 increased the luciferase activity, compared to the C allele. Discussion & Conclusions These results indicate, a promoter SNP rs374810 of RSPO2 may be involved in the susceptibility of schizophrenia, increasing the promoter activity of RSPO2. The limitation of this study is that only 6 Wnt signaling genes were tested. We could not examine all the genes involving Wnt signaling. Nevertheless, this study proposed RSPO2 as the new candidate gene for schizophrenia and detected the activity of the promotor SNP of the gene. Future research studies using cellular and animal models are needed to fully characterize the function of RSPO2 in the pathophysiology of schizophrenia. In conclusion, RSPO2 in Wnt signaling pathway might be one of several genes that may be associated with susceptibility to schizophrenia in the Korean population.