Genetic association and identification of a functional SNP at GSK3β for schizophrenia susceptibility

Objective: GSK3 beta is a key gene in neurodevelopment, and also an important target of antipsychotics. Several lines of evidence including association and gene expression studies have suggested GSK3 beta as a susceptibility gene for schizophrenia, but the underlying genetic mechanism is still unknown. In this study, we test whether the genetic variants in GSK3 beta contribute to the risk of schizophrenia in Chinese population. Methods: We first conducted an association analysis of 9 representative SNPs spanning the entire genomic region of GSK3 beta in two independent Han Chinese case-control samples from southwestern China (the Kunming sample and the Yuxi sample, a total of 2550 subjects).Then using EMSA and reporter gene assays, we tested the functional impact of the identified risk SNP on transcriptional factor binding affinity and promoter activity. Results: We observed weak allelic associations of three GSK3 beta SNPs (rs3755557, rs7431209 and rs13320980) with schizophrenia in the combined Han Chinese samples. Further analysis using genotypes (under recessive genetic model) supported the association of rs3755557 (p = 0.01, corrected), which is located in the GSK3 beta promoter region. The functional assays demonstrated that the risk SNP (rs3755557) could influence the transcription factor binding affinities, resulting in a higher promoter activity of the risk allele. Conclusion: Our findings suggest that GSK3 beta is likely a risk gene for schizophrenia, and its expression alteration caused by the risk SNP in the promoter region may contribute to the etiology of schizophrenia. (C) 2011 Elsevier B.V. All rights reserved.