中科院昆明动物研究所比较基因组学实验室宿兵研究员实验室继研究揭示一个新的ZNF804A功能突变可能是中国人群中导致精神分裂症发生的重要遗传因素之一的成果之后，通过与昆明医学院第一附属医院、云南省精神病医院和玉溪市第二人民医院合作研究表明，rs3755557的风险等位基因能够增强GSK3B基因的启动子活性，这与前人在小鼠体内的过表达GSK3B基因的研究结果是一致的。该研究证实了GSK3B在中国人群中也是精神分裂症易感基因。
精神分裂症是困扰人类的重大精神疾病之一，双生子研究和领养研究证实，精神分裂症具有很强的遗传力(>80%)。近年来，随着研究手段的不断成熟以及样本量的逐渐增大，越来越多的精神分裂症易感基因被报道出来。
GSK3B基因是首先在欧洲人群通过连锁分析发现的一个精神分裂症易感基因。然而，随后在世界范围人群的验证研究却报道了不一致的结果。为了探究GSK3B基因在中国人群中是否是精神分裂症的易感基因，中国科学院昆明动物研究所宿兵研究员实验室（博士研究生李明）通过与昆明医学院第一附属医院、云南省精神病医院和玉溪市第二人民医院合作，对昆明和玉溪的2,550份病例-对照样本进行了系统的遗传学分析。
研究发现，在GSK3B基因的启动子区的一个序列多态性位点 (rs3755557) 在研究的云南样本中与精神分裂症相关。这个位点在之前被欧洲研究小组和韩国研究小组报道过，但是并不与精神分裂症相关，这可能是人群的遗传背景异质性以及之前研究的样本量偏小的原因。随后，他们对rs3755557进行了功能预测，发现这个位点可能会影响GSK3B基因的启动子活性，并通过凝胶阻滞实验和双荧光报告系统证实了这一猜测。
相关英文论文摘要：
Genetic association and identification of a functional SNP at GSK3β for schizophrenia susceptibility
OBJECTIVE: GSK3β 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 GSK3β as a susceptibility gene for schizophrenia, but the underlying genetic mechanism is still unknown. In this study, we test whether the genetic variants in GSK3β 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 GSK3β 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 GSK3β 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 GSK3β 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 GSK3β 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.
英文论文原文：https://www.medlive.cn/uploadfile/2011/1020/20111020024012929.pdf
