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）的特点是早期出现的社会交往障碍和精神障碍