An ASD Enriched Risk (ASD-ER) ECHO Cohort

ASD 丰富风险 (ASD-ER) ECHO 队列

• 批准号: 10241957
• 负责人: KRISTEN Lyall
• 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/10241957
• 关键词: Address; Advocate; Affect; Age; Area; Behavior; Biological; Biological Markers; Brain; Categories; Child; Collection; Complex; Consent; Data; Dental; Deposition; 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; 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; detection method; 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会交往障碍， 在存在限制和刻板的兴趣或行为的情况下进行交流。ASD的患病率在 美国约为1.5%，使其成为最常见的严重神经发育状况， 在美国，与ASD相关的成本超过2500亿美元。2儿童神经发育是 ECHO倡议和ASD显然是主要公共卫生关注神经发育结果。 虽然已知遗传因素会影响ASD风险，但其潜在机制相当复杂， 多方面的证据表明，环境风险因素发挥了作用。大约20%的兄弟姐妹 患有ASD的儿童会自己发展ASD，高达40%的ASD兄弟姐妹会表现出某种类型的自闭症症状。 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， 揭示了ASD儿童的兄弟姐妹，他们的遗传背景可能富含低至中度 频率ASD风险基因型，形成强有力的候选人群，在其中调查候选ASD 可能与遗传易感性相互作用的环境因素。人们早就知道， 化学物质影响大脑发育，即使在低水平-与胎儿发育是一个窗口，特别是 易损性.在这里，我们建议组装一个ECHO儿科队列（称为ASD-ER 队列）包括1，713名ASD儿童的兄弟姐妹，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，并为更广泛的研究做出贡献 欧盟人道处倡议的使命。我们将收集脱落的乳牙从儿童和雇用最近 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。这些暴露数据将用于频率论和贝叶斯分析 评估不同时间窗内产前暴露对连续、分类和 轨迹ASD相关结果。儿童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和自闭症特异性遗传风险评分，以最大限度地提高我们的能力， 检测产前持久性有机污染物和金属暴露造成的风险。然后，因为在ECHO中包括ASD-ER受试者， 也将改变，并丰富右尾，维度ASD相关的神经发育特征分布在 ECHO研究人群，我们主张通过进行基因环境范围内的 互动研究（GWIS）的ASD和相关结果在整个ECHO队列，并概述了一种方法， 实施这个。ASD-ER的独特特征（队列的丰富风险性质结合 所有受试者均已完成深层神经发育表型分析， 基因组数据加上亚组上广泛的库存产前生物样品）与 更大的ECHO努力，可以将联合收割机与真正创新科学的众多机会结合起来。