PCCβ介导的能量代谢通路在精神分裂症中的作用及调控机制

Schizophrenia is a chronic and severe mental disorder, and our current knowledge of the etiology and molecular mechanisms is limited. Our research group has carried out a largest ever trans-ethnic genetic study of schizophrenia (published in Nat. Genetics). The results showed that the 3q22.3 region was significantly associated with schizophrenia in both Chinese and European populations. Comprehensive analyses showed that it may be involved in the pathology through down-regulation of PCCB gene expression, which was initially confirmed by preliminary experiments. Based on these findings, we will carry out a further fine mapping research on the schizophrenia susceptibility locus (3q22.3 region) by using AmpliSeq and our self-developed long-range haplotype inference algorithm (PLCSEM), as well as QTL analyses for key traits. We will try to find out the pathogenic functional mutations of schizophrenia in the susceptibility locus. We will also perform a series of functional experiments to analyze the biological functions of the pathogenic mutations, and to unravel the roles of PCCβ-mediated energy metabolism pathways and their abnormalities in molecular mechanisms of schizophrenia. Our study is expected to reveal the new pathogenesis of schizophrenia and enrich the understanding of the genetic mechanisms of schizophrenia. The findings will provide theoretical basis for personalized and precision medicine of the disease.

精神分裂症是一类严重的致残性精神疾病，目前对其病因及分子机制的理解有限。申请人前期开展了迄今国际最大规模的精神分裂症跨种族遗传学研究（论文发表于Nature Genetics），研究结果表明3q22.3区域在不同种族中均与精神分裂症显著关联，综合分析显示其最可能通过下调PCCB基因表达参与疾病发生过程，并在预实验中得到初步确认。基于这些研究成果，本项目拟（1）应用靶向扩增子测序技术（AmpliSeq）、长片段单倍型分析算法PLCSEM（自主开发）等技术对3q22.3区域进行精细定位分析，并结合关键性状QTL分析，鉴定该区域的精神分裂症致病功能性突变；（2）通过一系列功能实验分析致病功能性突变的生物学功能，并深入解析PCCβ介导的能量代谢通路及其异常在精神分裂症分子病因的作用机制。本研究有望揭示全新的精神分裂症发病机制，丰富对精神分裂症遗传机制的认识，为疾病的个性化、精准医疗提供理论依据。

精神分裂症是一类严重的致残性精神疾病，目前对其病因及分子机制的理解有限。我们在前期研究基础上进一步开展了3q22.3等精神分裂症易感区域的功能性SNPs分析，锁定351个候选功能位点开展STARR-seq实验增强子活性，确定rs13072690为3q22.3易感区域内的调控功能突变；构建了pccb、ddhd2等基因敲除斑马鱼模型，分析了致病基因的生物学意义，初步分析了其参与疾病发生发展的分子机制。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，并开发了指导药物使用的分析方案并取得了专利授权。我们分析了血源DNA的嵌合染色体变异和精神分裂症之间的相关性，发现了精神分裂症患者的嵌合染色体变异负荷显著增加；还通过孟德尔随机化研究，分析吸烟行为对精神分裂症发生风险的影响。总体上，本项目从多个视角揭示精神分裂症的分子机制，为疾病的个性化、精准医疗奠定了重要基础，也理解精神分裂症的病因提供了新的方向。