近年来精神分裂症(SCZ)全基因组关联研究(GWAS)报道了多个疾病易感基因/位点，但各研究难以彼此验证。本项目首先基于前期完成SCZ的GWAS数据与千人基因组计划数据库及国际SCZ的GWAS数据进行预测插补(imputation)后比对和meta分析，并通过生物通路及SKAT等分析方法，探索高度关联易感基因/位点组合与疾病(内)表型组合的关联；继而在独立的SCZ病例与对照样本中，采用Sequenom检测方法验证meta分析发现的高度关联易感基因及基因型-表型组合的对应关系；在SCZ核心家系中，采用MiSeq测序筛选出高度关联染色体区的罕见变异，并进行外周血mRNA检测和eQTL分析；最后在SCZ尸脑标本中进行易感基因的表达检测及RNA-Seq分析，通过基因操作动物和细胞实验研究易感基因的潜在功能。本项目预期结果为进一步发现SCZ高度关联易感基因/位点(组合)并阐释其发病机制提供线索。

Recent literatures showed that the genome-wide association study (GWAS) of schizophrenia have been reported across several populations. However, up to now there was no susceptibility genes have been validated clearly and consistently across various studies. Based on the literature review and our previous research of GWAS data in Chinese Han population in schizophrenia, we intended to make a meta-analysis post-GWAS of schizophrenia. The imputation will be made both in our GWAS data of Chinese Han (Illumina 610K and Omni8-Zhonghua SNP arrays) and European GWAS (PGC and Sweden) by using the 1000 genome project (1KGP) data. Then the meta analysis of GWAS will be implemented by using the Metal software. On the other hand, bioinformatics analysis will include the pathway-based, SKAT or community-based analyses, as well as eQTL and ENCODE functional prediction at the GWAS level. The meta-analysis results will be validated in 2000 independent schizophrenic patients and 2000 healthy control subjects by using the Sequenom MassArray genotyping platform. Another 50 parent-offspring trios of schizophrenia will also be examined by using the exon sequencing to validate the highly associated chromosome regions of meta-analysis results. The Atlas BrainSpain database and the postmortem brain tissues of schizophrenic patients from the Lieber Institute for Brain Development (LIBD), USA, will be used to explore the eQTL pattern of susceptibility genes. Potential functional exploration of susceptibility genes of schizophrenia will primarily include in situ hybridization, in utero electroporation, RNAi, and other techniques. The results will be helpful to interpret the mechanism or pathogenesis of schizophrenia.