精神分裂症易感基因DDHD2的致病功能变异鉴定及机制研究

Schizophrenia is a mental disorder characterized by a deep disruption of emotional response and thinking process, and it’s one of the most serious and frightening of all mental illnesses. Our research group has carried out a genome-wide association study (GWAS) of schizophrenia in the Han Chinese population and identified 8p12 as a novel schizophrenia risk locus (published in Nature Genetics), and the association was replicated in the European population. We speculate that DDHD2 is likely to be the most important susceptibility gene in this region (the top susceptibility variant G>C-1433) after the data were exploited deeply and extensively. Based on these findings, we will carry out a further fine mapping research on DDHD2 gene of schizophrenia by using PCR Amplicon and next-generation sequencing (NGS) technologies, with combination of our self-developed long-range haplotype inference algorithm (PLCSEM). We will try to find out the causative variants of schizophrenia in the susceptibility gene, and validate the findings by functional experiments for further understanding the molecular mechanisms of the candidate variants. Our study will shed new light on elucidating the etiology of schizophrenia as well as personalized and precision medicine.

精神分裂症（Schizophrenia）是一种以情感反应与思维过程发生深度混乱为主要特征的精神障碍。项目组前期开展的汉族人群全基因组关联分析发现了新的精神分裂症易感区域8p12（论文发表于Nat. Genetics杂志），且在欧洲人群中得到进一步确认。我们对数据进行深入挖掘后进一步锁定DDHD2为区域内重要易感基因（关键易感突变G>C-1433）。基于这些研究成果，本课题拟（1）应用扩增子（Amplicon）及新一代测序（NGS）技术对DDHD2基因的启动子区、UTR及CDS区域进行深度测序，同时结合自主开发的长片段单倍型推断算法（PLCSEM），鉴定精神分裂症的致病功能性突变；（2）开展功能实验探索DDHD2基因参与精神分裂症发病的分子机制。本研究有望发现精神分裂症新的致病功能位点，进一步揭示精神分裂症发病的分子遗传机制，为疾病的个性化、精准医疗提供理论依据。

遗传因素在精神分裂症的发展中起重要作用，目前对其病因的了解仍然有限，有很大比例的遗传风险因素还有待探索。我们通过中欧跨种族荟萃分析进一步明确了8p12与精神分裂症的相关性，并通过精细定位分析锁定了区域内的多个编码和调控功能变异。我们的跨种族分析证明了跨人群荟萃分析对于精神分裂症位点精细定位分析的附加价值，并突出显示了不同人群共有遗传风险的存在。我们发现了30个新的精神分裂症风险位点，并突出了能量代谢等值得进一步深入研究的关键通路，进一步通过孟德尔随机化分析，证实了高空腹胰岛素水平的遗传易感性与精神分裂症风险增加有因果关系。通过药物基因组学分析，我们鉴定了多个与精神分裂症药物不良反应相关位点，并证实了其对基因转录活性的影响。总体上，本项目从多个视角揭示精神分裂症的分子遗传机制，为精神分裂症的病因提供了进一步的生物学见解，也为疾病的个性化、精准医疗奠定了理论依据。