Population-Based Autism Genetics and Environment Study

基于人群的自闭症遗传学和环境研究

• 批准号: 9897843
• 负责人: Joseph D. Buxbaum
• 金额: $ 15.98万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897843
• 关键词: 22q11; 22q13; Address; Affect; Age; Agreement; Architecture; Biological; Bipolar Disorder; Birth; Blood; Clinical Data; Clinical Trials; Collection; Control Groups; Copy Number Polymorphism; County; DNA; DSM-IV; Data; Data Sources; Databases; Diagnosis; Discipline of obstetrics; Disease; Dissection; Environment; Environmental Risk Factor; Epidemiology; Etiology; Family Relationship; Foundations; Frequencies; Future; Generations; Genetic; Genetic Models; Genotype; Geographic Locations; Government; Grant; Heritability; Individual; Infrastructure; Inherited; International; Intervention; Matched Group; Medical; Medical History; Mental disorders; Methods; Mission; Modeling; Nature; Neurodevelopmental Disorder; Nucleotides; Obstetric Delivery; Parents; Patients; Pilot Projects; Population; Positioning Attribute; Prevention; Public Health; Recommendation; Recurrence; Registries; Research; Research Personnel; Resources; Risk; Risk Estimate; Risk Factors; Role; SNP array; SNP genotyping; Saliva; Sampling; Schizophrenia; Source; Sweden; System; Twin Studies; United States National Institutes of Health; Variant; Venous; Vital Status; autism spectrum disorder; base; biobank; case control; database of Genotypes and Phenotypes; delivery complications; density; disorder risk; epidemiology study; exome; exome sequencing; experimental study; genetic analysis; genetic linkage analysis; improved; innovation; non-genetic; novel; population based; risk sharing; severe psychiatric disorder; sex

Project Summary/Abstract While there has been great progress in understanding the risk architecture of autism, there are still unanswered questions about the nature of the genetic and non­genetic risk for autism. Many of these questions can be best addressed with a population­-based epidemiological sample with detailed demographic and environmental information. To date, almost all studies on the etiology of autism relied on convenience samples, which are subject to biases in capturing genetic and, possibly even more so, environmental risk. Epidemiologically based samples provide a unique resource to identify genetic and non­genetic causes of autism, while allowing for a precise estimate of risk in the population attributed to each source of risk. Sweden benefits from a centralized medical system that has been the foundation of large­scale epidemiological studies in psychiatric disorders, particularly schizophrenia and bipolar disorder. In our opinion, the significance of this proposal lies in the value of a unique, population-­based epidemiological sample, analyzed in such a way as to address several outstanding issues in autism. These include: 1) Better estimates of heritability and environment in autism? 2) assessing the rate of recurrent risk CNV in autism? 3) discovery of rare standing single nucleotide variation in autism? 4) dissection of mechanisms underlying the association of non-genetic findings with autism – and the discovery of novel environmental associations? and, 5) cross-­disorder analyses to better understand shared liability to autism and schizophrenia. The aims are: 1) To ascertain and biobank at least 1300 cases with autistic disorder and 1000 additional controls, to develop an international resource for ASD, and to assess selected, putative risk factors? 2) To genotype all samples using high­-density SNP arrays, including dense exome coverage, and sequence all trios using whole ­exome approaches? and, 3) To use novel methods to assess the role of inherited and de novo variants in autism and to evaluate rare standing variation in autism, while integrating key environmental variables. In later years the relationship between autism risk and risk for schizophrenia will be assessed. The proposed research is innovative, in our opinion, because it ascertains autism samples in an epidemiologically-­valid manner, targeting a genetically homogenous population, for which schizophrenia and bipolar samples have already been collected. The proposal is also innovative in the use of novel methods to estimate heritability and to identify rare, standing ­variation conferring risk to autism, while providing an integrated model for genetics and environment in autism. Finally, the application is innovative, in our opinion, in that it provides the groundwork for understanding shared risk across autism and schizophrenia, making use of a homogenous group to have better power to identify shared risk. This new and substantively different approach to studying autism, compared to studies carried out in convenience samples, addresses many of the open questions in autism research and provides a path towards a better understanding of the risk factors for autism and ultimately to better interventions in autism.

项目概要/摘要 尽管在了解自闭症风险结构方面取得了很大进展，但仍然存在一些问题 关于自闭症的遗传和非遗传风险的性质，其中许多问题尚未得到解答。 可以通过基于人群的流行病学样本以及详细的人口统计数据来最好地解决问题 迄今为止，几乎所有关于自闭症病因的研究都依赖于便利。 样本在捕获遗传风险和环境风险方面可能存在偏差。 基于流行病学的样本为识别遗传和非遗传原因提供了独特的资源 自闭症，同时可以精确估计瑞典每个风险来源的人群风险。 受益于作为大规模流行病学研究基础的集中医疗系统 我们认为，这对于精神疾病，特别是精神分裂症和双相情感障碍具有重要意义。 提案的价值在于独特的、基于人群的流行病学样本的价值，并以这样的方式进行分析： 解决自闭症的几个突出问题，其中包括：1）更好地估计遗传性和环境。 2) 评估自闭症复发风险 CNV 的发生率？ 3) 发现罕见的单核苷酸？ 自闭症的变异？4）剖析非遗传发现与自闭症关联的机制—— 以及新的环境关联的发现？5）跨疾病分析以更好地理解 自闭症和精神分裂症的共同责任 目标是： 1) 确定至少 1300 例病例并进行生物样本库。 患有自闭症障碍和 1000 项额外控制，开发 ASD 国际资源，并评估 选定的假定风险因素？ 2) 使用高密度 SNP 阵列（包括密集型）对所有样本进行基因分型 外显子组覆盖，并使用全外显子组方法对所有三组进行测序？以及，3）使用新方法来 评估遗传性变异和新发变异在自闭症中的作用，并评估自闭症中罕见的长期变异， 在随后的几年中，我们整合了关键的环境变量，并研究了自闭症风险与风险之间的关系。 我们认为，拟议的研究具有创新性，因为它确定了精神分裂症。 以流行病学有效的方式对自闭症样本进行采样，针对遗传同质人群，其中 该提案在使用方面也具有创新性。 估计遗传力和识别罕见的、持续的变异赋予自闭症风险的新方法，同时 最后，该应用程序具有创新性，为自闭症的遗传学和环境提供了一个综合模型。 我们认为，它为理解自闭症和精神分裂症的共同风险奠定了基础， 利用同质群体有更好的能力来识别这种新的、实质性的风险。 与在方便样本中进行的研究相比，研究自闭症的不同方法解决了 自闭症研究中的许多悬而未决的问题，并提供了更好地了解风险的途径 自闭症的影响因素，并最终更好地干预自闭症。