中国科学院昆明动物研究所机构知识库

精神分裂症是一种常见的与神经发育相关的疾病，具有很高的遗传力（约81%）。利用传统的遗传连锁分析以及近些年发展的芯片技术和高通量测序技术，有力地帮助研究人员在整个基因组范围内找寻精神分裂症易感基因。然而，在精神分裂症易感基因分析方面仍然存在一些问题： 1）在欧洲人群和东亚人群中全基因组关联分析的结果有很大的不同，是什么原因造成了这种群体异质性？ 2）精神分裂症易感基因在网络水平上的特征是什么？ 3）根据目前的已有数据，如何去发现新的精神分裂症易感基因？本博士论文的研究工作就是围绕这些问题开展的，包括如下三个部分的研究内容： 1）欧亚人群间存在如此强的群体异质性表明群体历史的不同可能会对精神分裂症的易感性有所影响。我们分析了 136 个达到全基因组水平显著的单核苷酸多态位点（ SNP）在欧亚群体中等位基因频率的分化程度。我们的结果表明TSNAP18 基因上有两个 SNP 位点（ rs11038167 和 rs11038172）在欧亚群体之间存在明显的分化，在欧洲群体中等位基因几乎是单态的，但在东亚人群中杂合度很高，且这两个位点在中国汉族人群中达到全基因组水平显著。为了研究TSPAN18 基因在东亚人群里面的进化历史，我们进行了一系列的群体遗传学分析，包括经典的中性检验、基于单倍型的自然选择检测-整合单倍型分数（ iHS）、单倍型延伸纯合度分析（ EHH）、单倍型二分叉图和单倍型网络分析。我们发现rs11038172 上的保护碱基（ G 等位基因）相对于 A 等位基因来说在东亚人群中有更长的延展单倍型；单倍型网络分析表明携带 G 等位基因的单倍型在东亚人群中呈现星状结构，表明这个单倍型在东亚人群中在最近有一个快速富集的过程。这些证据表明 rs11038172 的保护碱基 G 等位基因在东亚人群中受到了最近的自然选择作用。我们的发现为解释精神分裂症易感基因在欧洲和东亚人群的遗传异质性提供了一个新的视角。 2）为了在系统生物学层面对精神分裂症易感基因有一个全面了解，我们从9 个蛋白相互作用数据库中收集蛋白相互作用数据，计算了精神分裂症易感基因在网络中的参数特征。我们发现精神分裂症易感基因与基因组背景基因相比具有更高的度, 更高的接近中心性、更高的介数、更高的聚合系数以及更短的最短路径。这个结果表明精神分裂症基因在网络上的紧密关系。我们进一步发现精神分裂症易感基因能形成一个由 842个节点和 2,860条边构成的相互连接的蛋白相互作用网络（ p=4.15E-31）。我们认为这个网络是精神分裂症的核心疾病网络。在该疾病网络中的枢纽基因（与之相互作用的蛋白中至少有 20 个精神分裂症易感基因）倾向于有显著的直接相互作用关系。我们从该疾病网络中提取了 4 个紧密相互作用的模块，功能富集（ GO）分析表明这些模块参与细胞间连接、免疫反应、GABA 受体和细胞周期过程，与精神分裂症密切相关。我们的结果显示，精神分裂症易感基因在蛋白相互作用水平上有模块化的特点；同时，我们也揭示了一些与精神分裂症相关的生物学过程。 3）为了发现新的精神分裂症易感基因，我们采用了整合分析的方法，包含蛋白相互作用分析、代谢通路的富集分析、表达分析以及全基因组关联分析。我们的结果表明 ATXN1是与已知精神分裂症易感基因 ZNF804A唯一有相互作用的蛋白；同时， ATXN1 还和其他 18 个已知的精神分裂症易感基因存在直接的蛋白相互作用。 ATXN1 在网络中也是一个枢纽基因，它的蛋白相互作用网络富集在MAPK 信号通路。进一步的表达分析表明， ATXN1 在人类大脑前额叶区高表达，并且在精神分裂症病人和对照间存在表达差异。我们通过分析已发表精神疾病的全基因组关联分析结果，证实 ATXN1 不仅与精神分裂症的发病相关，还与其他精神疾病相关，尽管这些相关性并没有达到全基因组显著水平。这些证据都一致支持ATXN1 是一个新的精神分裂症易感基因，整合分析方法是一个有效的研究精神疾病遗传基础的工具 

Schizophrenia (SCZ) is a common neurodevelopmental disorder with high heritability of approximately 81%. Traditional linkage studies and recent analyses using high-throughput genotyping and next generation sequencing technologies have greatly facilitated discovery of SCZ risk genes at genome wide level. However, there are still unanswered questions in studies of SCZ risk gene: 1) Most of the identified susceptibility variants are population-specific to either Europeans or East Asians. What are the reasons behind the strong genetic eterogeneity of SCZ risk genes in different populations? 2) What is the network property of SCZ genes? 3) How to identify new SCZ genes based on current data? We attempted to tackle these questions using different approaches and the results include the following three parts: 1) The strong genetic heterogeneity between Europeans and East Asians suggests that differential population histories may play a role in SCZ susceptibility. We explored the allele frequency divergence of 136 previously reported genome-wide SCZ risk SNPs between European and East Asian populations. Our results showed that two SNPs (rs11038167 and rs11038172) at TSPAN18, reported as genome-wide significant SCZ risk variants in Han Chinese, were entirely monomorphic in Europeans, indicating a deep between-population divergence at this gene locus. To explore the evolutionary history of TSPAN18 in East Asians, we conducted population genetic analyses including multiple neutrality tests, the haplotype-based iHS and EHH tests, as well as haplotype bifurcation map and network constructions. We found that the protective allele of rs11038172 (G allele) had a long-extended haplotype with much slower decay compared to the A allele. The star-like shape of the G-allele-carrying haplotypes indicates a recent enrichment in East Asians. Together, the evidences suggest that the protective allele of rs11038172 has experienced recent Darwinian positive selection in East Asians. These findings provide new insights that may help explain the strong genetic heterogeneity in SCZ risk and previous inconsistent association results for SCZ in Europeans and East Asians. 2) To understand SCZ gene at the systems-level, we investigated the parameter characteristics of SCZ genes in the interactome that we compiled from 9 protein-protein interaction (PPI) databases. Our result revealed that SCZ genes tend to have higher degree, closeness centrality, betweeness centrality, clustering coefficient, and shorter average shortest path length than background genes. This implicated a relatively close relationship of SCZ genes in the interactome. Furthermore, we found SCZ gene could formulate a well connected network that contains 842 nodes (SCZ risk genes) and 2,860 edges (p= 4.15E-31). This network may serve as the core SCZ disease network. In addition, we found SCZ hubs (SCZ genes that has more than 20 SCZ interacting partners) tend to have significantly direct interactions. We extracted 4 closely linked PPI interaction forms from the SCZ disease network, functional enrichment analysis (GO) of these modules indicate multiple processes, including cell adhesion, cell cycle, immune system response, and GABR-receptor complex that are associated with SCZ. Collectively, our results uncovered the module nature of SCZ risk genes in the PPI interactome, and there are several biological processes related to SCZ etiology. 3) With the use of an integrated approach combining PPI information with pathway and expression analysis as well as genome-wide association study (GWAS), we intended to find new risk genes for schizophrenia (SCZ). We showed that ATXN1 was the only direct PPI partner of the know SCZ risk gene ZNF804A, and it also had direct PPIs with other 18 known SCZ risk genes. ATXN1 serves as one of the hub genes in the PPI network containing many known SCZ risk genes, and this network is significantly enriched for the MAPK signaling pathway. Further gene expression analysis indicated that ATXN1 is highly expressed in prefrontal cortex, and SCZ patients had significantly decreased expression compared with healthy controls. Finally, the published GWAS data supports an association of ATXN1 with SCZ as well as other psychiatric disorders though not reaching genome-wide significance. These convergent evidences support ATXN1 as a promising risk gene for SCZ, and the integrated approach serves as a useful tool for dissecting the genetic basis of psychiatric disorders.