儿童孤独症遗传与环境交互作用的神经发育机制研究

Autism spectrum disorder (ASD) is the name for a group of developmental disorders. Both genetic and environmental factor contribute to the etiology of ASD which has a high prevalence and affect the health of children seriously. Common variation interacting with environmental factors is the pivotal mechanism of ASD, however, due to fewer study, the mechanism remains largely unknown. In this study, known ASD genetic, environmental, clinical database and ASD cohort data can be used to explore new biostatistics and statistical genetic method, expecting to control environmental variation and indentify possible environment-interacting ASD risk genes. By applying case only study and Two or multiple regression analysis, whole genome genetic and environment interacting study is launched. Also, new environment-interacting ASD risk genes can be indentified and the mechanism lying behind ULK4 and its interaction with environment can be illustrated. According to variations, knock out or BAC mouse model are constructed. As environmental factors are applied, the biological mechanism of ULK4 and other ASD risk genes interacting with environment can be illustrated. Furthermore, this study might provide basis for the development of the expected individualized risk environment prevention program, a basis for targeted treatment / prevention drug research and development, implementation of ASD precision medical care.

孤独症（自闭症）谱系障碍（ASD）是一组高发病率的神经发育障碍性疾病，严重影响儿童健康，遗传和环境因素是其主要病因。常见变异与环境因素交互作用是ASD重要的致病机制，由于起步较晚，其作用机制尚不清楚。本研究采用已建成的ASD遗传、环境、临床表型样本库和大样本ASD队列数据，探索新的生物统计和统计遗传学方法，以期控制环境变量，鉴定可能与环境因素交互作用的ASD新基因。采用Case only的研究设计，使用二项或多项回归分析，开展全基因组遗传与环境的交互作用研究，发现新的交互作用基因，并验证已鉴定的ULK4与环境可能存在的交互作用机制。根据遗传变异特点建立基因敲除或多拷贝表达的小鼠模型，并模拟环境因素，以期阐明ULK4等ASD风险基因与环境因素的交互作用对脑神经发育的影响及其致病的生物学机制。为制定孕期个体化危险环境预防方案提供依据，为靶向治疗/预防药物研发、实施ASD精准医疗提供重要基础。

孤独症谱系障碍（ASD）是一组严重影响儿童健康的神经发育障碍性疾病，遗传和环境因素是其主要病因。遗传与环境因素交互作用是ASD重要的致病机制，但其作用机制尚不明确。本研究结合项目组前期建成的ASD临床-遗传-环境资源库和大规模ASD基因组学数据，通过生物信息学、模型小鼠和神经生物学多种技术手段开展ASD遗传与环境风险因素的交互作用机制研究，取得的主要结果如下：1）完善和扩充建立中国人群ASD临床-遗传-环境资源库，发现多个与ASD发生相关环境因素（母孕期化学物暴露和孕期高血压等）及其与遗传的交互作用；2）发现新的中国ASD患者风险基因突变谱和隐性遗传基因，描绘多个ASD高风险基因分子亚型；3）发现了多个调控叶酸、催产素相关ASD遗传-环境易感基因集，构建基因-环境交互作用分析模型；4）发现调控应激颗粒关键基因CSDE1、UBAP2L遗传变异与参与ASD发生，揭示应激颗粒介导基因-环境交互参与ASD风险的新机制。本项目顺利完成了研究内容，达到预期目标，研究结果为孤独症母孕期干预方案的制定和预警、遗传咨询及临床分子诊断提供科学依据。