精神分裂症全基因组水平的生物信息学分析与验证

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.

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。

项目组长期从事精神分裂症的遗传易感性研究，并致力于建立数据平台规范，取得以下学术成绩：1) 采用全基因组关联研究(GWAS)发现精神分裂症新易感基因，并开展东亚人群及亚欧跨种族精神分裂症易感基因的比较分析，进而初步解析易感基因的潜在神经生物学功能。2) 应用多组学研究分析策略，发现精神分裂症转录水平异常机制，进而发现遗传-环境风险因素的交互作用，通过大脑神经环路影响脑认知功能等高级功能。3) 大样本药物基因组学研究发现与抗精神病药疗效及不良反应个体化差异关联的新易感基因。4) 建立精神障碍临床研究科研协同平台和生物样本库系统。“精神疾病科研数据协同在线平台”的建设工作(http://www.h6world.cn/h6dp-web)，目前已完成了平台的框架构建工作和部分病例采集工作，并依托该项目进行了推广应用。发表SCI收录学术论著9篇，已修回3篇，相关内容未标注2篇；部分重要发现发表在Nat Genet, Lancet Psychiatry, Mol Psychiatry, Schizophr Bull, Sci Rep等杂志，在国际上产生了重要的学术影响。申请国家发明专利2项及软件著作权1项；与国内企业合作开发临床检测用药物靶向检测试剂盒一套，有较好的临床转化应用价值。