早发性精神分裂症患者核心家系的后GWAS分析

Schizophrenia is a kind of complex genetic diseases with many minor genes involved, and has 80% high heritability. It is the key problem for psychiatry to determine the susceptibility gene and explain the genetic mechanism of schizophrenia. There are some valuable informations provided by case-control genome-wide association studies (GWAS) for determining the susceptibility gene of schizophrenia. The results from case-control GWAS are affected by some factors, such as population stratification, design of chip, because of its own limitation. The well findings need support by other levels. Reduplication of case-control GWAS with large sample family trios is useful tool and important approach to improve the reliabity of the results from case-control GWAS. The early onset schizophrenia has more damage, poor treatment result and more possibility affected by genetic. In this study, a family-based association study was designed to confirm the association between schizophrenia and 50 SNPs selected from case-control GWAS of Han Chinese population in 500 early onset schizophrenia family trios from north Henan. Sequenom and Pyrosequencing assay will be performed for genotyping. Genetic analysis will be performed to investigate whether the SNPs are associated with schizophrenia in Han Chinese population. Neuropsychological tests will be carried out to assess the behavior personality of participator. Whether the hereditary variation affected neuropsychology will be analyzed. Family environment condition will be survey by scales Egma Minnen av Bardndosnauppforstran (EMBU) et al, the role of Gene-by-environment interaction will be estimated. This study will provide new evidences for schizophrenia genetic.

精神分裂症是一种多基因复杂疾病，遗传度高达80%。确定其易感基因有助于阐明其发病机制。全基因组关联分析（GWAS）为精神分裂症易感基因定位提供了有价值的信息，但结果易受人群因素等影响。采用相同遗传背景的大样本遗传家系对病例对照GWAS结果进行验证是提高GWAS结果可靠性的有效手段和重要途径。早发性精神分裂症危害更大、疗效更差、遗传易感性更显著。本课题组拟收集500个早发性、汉族精神分裂症患者核心家系，采用神经心理测验测试其行为和性格，采用父母教养方式量表等评估患者家庭社会心理特征，结合文献报道及课题组前期工作，从汉族精神分裂症GWAS结果中选取50个SNP位点，采用Sequenom、焦磷酸测序技术进行基因型检测，通过基于家系的遗传分析，确定这些SNP位点与汉族精神分裂症是否存在关联，分析遗传变异对神经心理的影响，分析基因与环境对其发病风险的相互作用。该结果有望为分裂症遗传学研究提供新证据。

精神分裂症（SZ）是一种多基因复杂疾病，。全基因组关联分析（GWAS）为精神分裂症易感基因定位提供了有价值的信息。采用不同层次的遗传样本对GWAS结果进行验证是提高GWAS结果可靠性的有效手段和重要途径。本研究进行了以下三方面工作：1、收集以早发精神分裂症家系为主的精神分裂症核心家系，并进行系统评估；2、结合GWAS结果选择精神分裂症候选基因，进行遗传关联研究，进行病例对照研究，共选取6个基因84个位点进行了分析；3、利用本项目建立的方法体系对急性一氧化碳中毒后迟发性脑病与NRXN3、PARK2两个精神疾病的共同候选基因的关联进行了研究。研究结果如下：. 收集428个患者起病年龄＜18岁的，汉族SZ核心家系，提取了428个核心家系、267个散发病例血液样本基因组DNA；5-羟色胺转运体基因（SLC6A4）rs140700位点SZ患者和对照组之间的基因型和等位基因频率存在显著差异，rs6352 SZ患者和对照组之间基因型频率显著的差异；雌激素受体基因α基因位点rs2234693和rs9340799单体型与SZ关联，rs2234693与患者首发年龄有关联；rs2234693不同基因型之间的冲动控制障碍症状分及其减分的比较差异具有统计学意义；NMDA受体2B基因（ GRIN2B）rs2098469、rs12319804 两个位点等位基因频率与SZ关联，rs2098469、 rs12820037和rs7298664基因型频率显著关联；MicroRNA137 rs66642155位点多态性与SZ患者起病年龄关联，不同基因型患者之间基线PANSS阳性症状分的差异均具有统计学意义；锌指蛋白ZNF804A基因rs1344706A/C变异基因型和等位基因频率在SZ患者和健康对照组中的分布均无显著性差异，基因型频率与不同的精神分裂症亚型之间存在显著相关性；NRXN3基因rs11845632和rs2196447、Parkin基因rs1784594位点在一氧化碳中毒后迟发性脑病（DEACMP）和急性CO中毒之间差异均有统计学意义，首次报道了神经发育相关基因与DEACMP这种器质性精神障碍的关联性，为该类研究提供了新的思路。.本项目为进一步工作收集了遗传样本，报道了SLC6A4、GRIN2B等新的SZ关联的基因变异，证实了ESRα、ZNF804A基因与临床症状等的关联，丰富了SZ的遗传机制。