Population-Based Autism Genetics & Environment Study

基于人群的自闭症遗传学

• 批准号: 8542900
• 负责人: Joseph D. Buxbaum
• 金额: $ 60.05万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-10 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542900
• 关键词: 22q11; 22q13; Address; Affect; Age; Agreement; Architecture; Autistic Disorder; Biological; Bipolar Disorder; Birth; 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; Epidemiologic Studies; Epidemiology; Etiology; Family Relationship; Foundations; Frequencies; Future; Generations; Genetic; Genetic Models; Genetic Risk; Genotype; Geographic Locations; Government; Heritability; Individual; Inherited; International; Intervention; Lead; Life; 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 Infrastructure; Research Personnel; Resources; Risk; Risk Estimate; Risk Factors; Role; SNP genotyping; Sampling; Schizophrenia; Source; Swab; Sweden; System; Twin Studies; United States National Institutes of Health; Variant; Venous blood sampling; Vital Status; autism spectrum disorder; base; biobank; case control; cost; database of Genotypes and Phenotypes; density; disorder risk; exome; exome sequencing; genetic analysis; genetic linkage analysis; improved; innovation; meetings; non-genetic; novel; population based; research study; risk sharing; sex

DESCRIPTION (provided by applicant): 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 non-genetic 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 non-genetic 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 large-scale 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 nongenetic 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.

描述（由申请人提供）： 尽管在了解自闭症风险结构方面已经取得了很大进展，但关于自闭症遗传和非遗传风险的性质仍然存在未解答的问题。其中许多问题可以通过基于人群的流行病学样本以及详细的人口和环境信息得到最好的解决。迄今为止，几乎所有关于自闭症病因学的研究都依赖于方便样本，这些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自闭症的遗传和非遗传原因提供了独特的资源，同时允许精确估计归因于每种风险源的人群风险。瑞典受益于中央医疗系统，该系统是精神疾病（特别是精神分裂症和双相情感障碍）大规模流行病学研究的基础。我们认为，该提案的意义在于独特的、基于人群的流行病学样本的价值，并通过分析的方式解决自闭症的几个突出问题。其中包括：1）更好地估计自闭症的遗传力和环境； 2）评估自闭症复发风险CNV的发生率； 3）发现自闭症中罕见的单核苷酸变异； 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) 确定并生物银行至少 1300 例自闭症患者和 1000 个额外对照，开发自闭症谱系障碍国际资源，并评估选定的假定风险因素； 2) 使用高密度 SNP 阵列对所有样本进行基因分型，包括密集的外显子组覆盖，并使用全外显子组方法对所有三组进行测序； 3) 使用新方法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，同时整合关键的环境变量。在以后的几年中，将评估自闭症风险和精神分裂症风险之间的关系。我们认为，拟议的研究具有创新性，因为它以流行病学上有效的方式确定了自闭症样本，针对的是基因同质人群，已经收集了精神分裂症和双相情感障碍样本。该提案在使用新方法来估计遗传力和识别罕见的、导致自闭症风险的常变方面也是创新的，同时提供了一种 自闭症遗传和环境的综合模型。最后，该应用程序具有创新性， 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，利用同质群体来更好地识别共同风险。与在方便样本中进行的研究相比，这种新的、本质上不同的自闭症研究方法解决了自闭症研究中的许多悬而未决的问题，并为更好地了解自闭症的风险因素并最终更好地干预自闭症提供了一条途径。