An ASD Enriched Risk (ASD-ER) ECHO Cohort

ASD 丰富风险 (ASD-ER) ECHO 队列

• 批准号: 10018528
• 负责人: Craig J Newschaffer
• 金额: $ 230.32万
• 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/10018528
• 关键词: Address; Advocate; Affect; Age; Area; Behavior; Biological; Biological Markers; Brain; Categories; Child; Collection; Complex; Consent; Data; Dental; Deposition; Detection; Development; Developmental Delay Disorders; Dimensions; Dose; Emerging Technologies; Environment; Environmental Epidemiology; Environmental Risk Factor; Estrogen receptor positive; 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; Pediatric cohort; 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; autistic children; 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)的特征是早期出现的社交障碍和 在存在受限和刻板印象的兴趣或行为的情况下进行的交流。自闭症在中国的患病率 美国约为1.5%，使其成为最常见的严重神经发育疾病，每年 在美国，与自闭症相关的成本超过2500亿美元。2儿童神经发育是 ECHO倡议和自闭症显然是主要公共卫生问题的神经发育结果。 虽然已知遗传因素影响ASD风险，但潜在的机制相当复杂，而且 多条证据表明，环境风险因素起到了一定的作用。大约20%的兄弟姐妹 患有自闭症的儿童会自己发展为自闭症，多达40%的自闭症兄弟姐妹会表现出某种类型的 不典型的神经发育。这明显支持了遗传易感性在ASD中的作用，但也 揭示了患有自闭症儿童的兄弟姐妹，他们的遗传背景可能丰富了低到中等水平 ASD风险基因型的频率，形成研究候选ASD的强大候选人群 可能与遗传易感性相互作用的环境因素。长期以来，人们就知道有毒的 化学物质即使在低水平也会影响大脑发育--胎儿发育是一个特殊的窗口 脆弱性。在这里，我们建议组装一组ECHO儿科队列(称为ASD-ER 队列)由1713名患有自闭症儿童的兄弟姐妹组成，他们在14岁时参加了5项研究 网站。ASD-ER将用于调查ASD的环境风险因素，并为更广泛的 回声倡议的使命。我们将收集儿童的乳牙脱落，并于近期聘用 能够对持久性有机污染物进行时间分辨量化的新兴技术 牙齿生物样本中的金属。这些曝光数据将用于频率分析和贝叶斯分析 评估不同时间窗的产前暴露对持续的、明确的和 轨迹ASD相关结果。儿童的遗传易感性将通过以下方式纳入我们的分析 开发和应用ASD和暴露特异性遗传风险评分，以最大限度地提高我们的能力 以检测因产前流行音乐和金属暴露而产生的风险。然后，因为在ECHO中包括ASD-ER受试者 也将移位并丰富ASD相关神经发育特征分布的右尾 回声研究群体，我们主张通过在整个基因环境中利用这一点。 全回声队列中ASD和相关结局的相互作用研究(GWIS)，并概述了一种方法 实施这一点。ASD-ER的独特特征(队列的丰富风险性质与 所有受试者已经完成的深层神经发育表型的可用性，并且很容易获得 基因组数据加上亚组上广泛储存的产前生物样本)覆盖了 更大的回声努力，可以结合到真正创新的科学的无数机会。