An ASD Enriched Risk (ASD-ER) ECHO Cohort

ASD 丰富风险 (ASD-ER) ECHO 队列

• 批准号: 9726807
• 负责人: Craig J Newschaffer
• 金额: $ 191.72万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9726807
• 关键词: Address; Advocate; Affect; Age; Area; Behavior; Biological; Biological Markers; Brain; Categories; Child; Childhood; Collection; Complex; Consent; Data; Dental; Deposition; Detection; Development; Developmental Delay Disorders; Dimensions; Dose; Emerging Technologies; Environment; Environmental Epidemiology; Environmental Risk Factor; Etiology; Evaluation; Exhibits; Exposure to; Fetal Development; Frequencies; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Impairment; Individual; Infant; Life; Measurement; Measures; Metal exposure; Metals; Methods; Mission; Modeling; Nature; Neurodevelopmental Disorder; Outcome; Participant; Pathogenicity; Perinatal Exposure; Phenotype; Poison; Polychlorinated Biphenyls; Population; Pregnancy; Prevalence; Procedures; Process; Protocols documentation; Public Health; Publications; Recurrence; Research Project Grants; Risk; Role; Sampling; Science; Siblings; Site; Social Interaction; Statistical Methods; Stereotyping; Subgroup; Symptoms; Tail; Technology; Time; Tissues; Tooth structure; autism spectrum disorder; cohort; cost; deciduous tooth; disorder risk; early life exposure; environmental chemical; experience; gene environment interaction; genetic epidemiology; genome-wide; genomic data; high risk; improved; innovation; interest; neurodevelopment; organochlorine pesticide; persistent organic pollutants; phthalates; postnatal; prenatal; prenatal exposure; prospective; research study; risk variant; social communication; study population; trait

Autism spectrum disorders (ASD) are characterized by early-emerging impairment in social interaction and communication in the presence of restricted and stereotyped interests or behaviors. The prevalence of ASD in the US is approximately 1.5%, making it the most common serious neurodevelopmental condition, and annual costs associated with ASD in the US exceed $250 billion.2 Child neurodevelopment is a priority outcome for the ECHO initiative and ASDs clearly are a neurodevelopmental outcome of major public health concern. While genetic factors are known to influence ASD risk, the underlying mechanisms are quite complex, and multiple lines of evidence suggest a role for environmental risk factors. Approximately 20% of siblings of children with ASD will develop ASD themselves and up to 40% of ASD siblings will show signs of some type of atypical neurodevelopment. This lends obvious support to the role of genetic susceptibility in ASD but also reveals how siblings of children with ASD, whose genetic backgrounds are likely enriched with low-to-moderate frequency ASD risk genotypes, form a strong candidate population in which to investigate candidate ASD environmental factors that likely interact with genetic susceptibility. It has long been known that toxic chemicals affect brain development even at low levels – with fetal development being a window of particular vulnerability. Here we propose to assemble an ECHO pediatric cohort-of-cohorts (referred to as the ASD-ER cohort) comprised of 1,713 siblings of children with ASD who have taken part in five research studies at 14 sites. ASD-ER will be used to investigate environmental risk factors for ASD and to contribute to the broader mission of the ECHO initiative. We will collect shed deciduous teeth from children and employ recently emerging technologies that enable temporally resolved quantification of persistent organic pollutants and metals in tooth biosamples. These exposure data will be used in both frequentist and Bayesian analytic frameworks to estimate effects of prenatal exposure in different time windows on continuous, categorical, and trajectory ASD-related outcomes. Child genetic susceptibility will be incorporated into our analyses through the development and application of ASD- and exposure-specific genetic risk scores in order to maximize our ability to detect risk due to prenatal POP and metal exposure. Then, because including ASD-ER subjects in ECHO will also shift, and enrich the right tail of, dimensional ASD-related neurodevelopmental trait distributions in the ECHO study population, we advocate for capitalizing on this by conducting a gene-environment wide interaction study (GWIS) for ASD and related-outcomes in the full ECHO cohort and outline an approach for implementing this. The unique features of ASD-ER (the enriched risk nature of the cohort combined with the availability of already-completed deep neurodevelopmental phenotyping on all subjects and readily available genomic data plus a wide range of banked prenatal biosamples on subgroup) overlaid with the scale of the larger ECHO effort, can combine to numerous opportunities for truly innovative science.

自闭症谱系障碍（ASD）的特征是社会互动和 在存在受限制和刻板印象的利益或行为的情况下进行交流。 ASD的患病率 美国约为1.5％，使其成为最常见的严重神经发育状况，并且年度 与美国ASD相关的成本超过2500亿美元。2儿童神经发育是优先结果 回声倡议和ASD显然是主要公共卫生关注的神经发育结果。 尽管已知遗传因素会影响ASD风险，但潜在机制非常复杂，并且 多种证据表明了环境风险因素的作用。约有20％的兄弟姐妹 患有ASD的儿童将自己成长为ASD，多达40％的ASD兄弟姐妹将显示某种类型的迹象 非典型神经发育。这为遗传易感性在ASD中的作用提供了明显的支持，但也为 揭示了ASD儿童的兄弟姐妹如何用低至中度的遗传背景丰富 频率ASD风险基因型，形成一个强大的候选人群，以研究候选ASD 可能与遗传敏感性相互作用的环境因素。早就知道有毒 化学物质即使在低水平上也会影响大脑发育 - 胎儿发育是特定的窗口 脆弱性。在这里，我们建议组装一个回声的小儿队列（称为ASD-ER） 队列）完成了1,713名ASD儿童的兄弟姐妹，他们参加了五项研究，当时是14个研究的五项研究 站点。 ASD-ER将用于调查ASD的环境风险因素，并为更广泛的 回声倡议的任务。我们最近将从儿童和员工那里收集棚子牙齿 能够暂时解决持续有机污染物和的新兴技术 牙齿生物样本中的金属。这些暴露数据将在频率和贝叶斯分析中使用 框架以估计不同时间窗口中产前暴露对连续，分类和 轨迹ASD相关的结果。儿童遗传易感性将通过我们的分析纳入我们的分析 ASD和暴露特定遗传风险评分的开发和应用，以最大程度地提高我们的能力 检测由于产前流行和金属暴露而引起的风险。然后，因为在Echo中包括ASD-ER受试者 还将转移并丰富与ASD相关的尺寸与ASD相关的神经发育特征分布 回声研究人群，我们主张通过进行基因环境来利用这一点 整个回声队列中的ASD和相关结果的交互研究（GWIS），并概述了一种方法 实施此功能。 ASD-ER的独特功能（同类的丰富风险性质与 在所有受试者上的已完成的深层神经发育表型的可用性，并且随时可用 基因组数据以及亚组上的广泛的银行产前生物样本）覆盖了 更大的回声努力可以结合到真正创新科学的众多机会。