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.

项目摘要/摘要 尽管在理解自闭症的风险架构方面取得了巨大进展，但仍有 关于自闭症的遗传和非遗传风险的性质的未解决的问题。其中许多 可以最好用基于人群的流行病学样本和详细的人口统计学来解决问题 和环境信息。迄今为止，几乎所有关于自闭症病因的研究都依赖于便利性 样品在捕获遗传方面存在偏见，甚至可能是环境风险。 基于流行病学的样本提供了独特的资源，以识别 自闭症，同时允许对每种风险来源的人口进行精确估计。瑞典 从已成为大规模流行病学研究的基础的集中医疗系统中受益 我们认为，这一点的意义 提案在于一个基于人群的独特流行病学样本的价值，以一种方式分析 解决自闭症中的几个杰出问题。其中包括：1）更好地估计遗传力和环境 在自闭症中？ 2）评估自闭症中复发风险CNV的速度？ 3）发现罕见的站立单核苷酸 自闭症的变化？ 4）解剖非遗传发现与自闭症相关的机制 - 并发现新颖的环境协会？ 5）跨disorder分析以更好地理解 对自闭症和精神分裂症的责任。目的是：1）确定和生物库至少1300例 加速疾病和1000个其他控件，为ASD开发国际资源，并评估 选择的，推定的危险因素？ 2）使用高密度SNP阵列的所有样品基因型，包括密集 外部覆盖范围，并使用整个外部方法对所有三重奏进行顺序？ 3）使用新颖的方法 评估自闭症中遗传变种和从头变异的作用，并评估自闭症的罕见立场变化， 同时集成了关键的环境变量。在后来的几年中，自闭症风险与风险之间的关系 精神分裂症将被评估。在我们看来，拟议的研究是创新的，因为它确定了 自闭症以流行病学的方式样本，针对普通同质的人群，为此 精神分裂症和双极样品已经收集。该提议在使用方面也是创新的 估计遗传力并确定自闭症的罕见，常规变异会议风险的新方法，而 为自闭症中的遗传学和环境提供综合模型。最后，应用程序是创新的，在 我们的观点，因为它为理解自闭症和精神分裂症的共同风险提供了基础， 利用同质群体有更好的能力来识别共同的风险。这个新的和实质性的 与在方便样本中进行的研究相比，研究自闭症的不同方法，地址 自闭症研究中的许多开放问题，为更好地理解风险提供了途径 自闭症的因素，最终是更好地干预自闭症的因素。