Genetic association and identification of a functional SNP at GSK3β for schizophrenia susceptibility
Genetic association and identification of a functional SNP at GSK3β for schizophrenia susceptibility
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精神分裂症易感性 GSK3β 功能性 SNP 的遗传关联和鉴定
DOI：
10.1016/j.schres.2011.09.013
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发表时间：
2011-12-01
影响因子：
4.5
通讯作者：
Su, Bing
中科院分区：
文献类型：
--
作者：
Li, Ming;Mo, Yin;Su, Bing
目的：GSK3 β是神经发育的关键基因，也是抗精神病药物的重要作用靶点。包括关联和基因表达研究在内的多项证据表明GSK 3 β是精神分裂症的易感基因，但其潜在的遗传机制仍不清楚。在本研究中，我们检验了中国人群中GSK3 β基因变异是否与精神分裂症的风险有关。方法：我们首先对来自中国西南地区的两个独立的汉族病例对照样本中的9个代表性的SNP进行了关联分析，这些SNP跨越了GSK 3 β的整个基因组区域（昆明样本和玉溪样本，共2550名受试者），然后采用EMSA和报告基因分析方法，检测所识别的风险SNP对转录因子结合亲和力和启动子活性的功能影响。我们观察到三个GSK 3 β SNPs（rs3755557，rs7431209和rs13320980）与精神分裂症合并汉族样本的弱等位基因关联。使用基因型的进一步分析（在隐性遗传模型下）支持rs3755557（p = 0.01，校正）的关联，其位于GSK 3 β启动子区域。结论：GSK3 β可能是精神分裂症的一个危险基因，其启动子区域的风险SNP（rs3755557）引起的GSK3 β表达的改变可能与精神分裂症的发病有关。(C)2011爱思唯尔有限公司版权所有。
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.