Autism spectrum disorders (ASD) are characterized by early-emerging impairment in social interaction andcommunication in the presence of restricted and stereotyped interests or behaviors. The prevalence of ASD inthe US is approximately 1.5%, making it the most common serious neurodevelopmental condition, and annualcosts associated with ASD in the US exceed $250 billion.2 Child neurodevelopment is a priority outcome forthe 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, andmultiple lines of evidence suggest a role for environmental risk factors. Approximately 20% of siblings ofchildren with ASD will develop ASD themselves and up to 40% of ASD siblings will show signs of some type ofatypical neurodevelopment. This lends obvious support to the role of genetic susceptibility in ASD but alsoreveals how siblings of children with ASD, whose genetic backgrounds are likely enriched with low-to-moderatefrequency ASD risk genotypes, form a strong candidate population in which to investigate candidate ASDenvironmental factors that likely interact with genetic susceptibility. It has long been known that toxicchemicals affect brain development even at low levels – with fetal development being a window of particularvulnerability. Here we propose to assemble an ECHO pediatric cohort-of-cohorts (referred to as the ASD-ERcohort) comprised of 1,713 siblings of children with ASD who have taken part in five research studies at 14sites. ASD-ER will be used to investigate environmental risk factors for ASD and to contribute to the broadermission of the ECHO initiative. We will collect shed deciduous teeth from children and employ recentlyemerging technologies that enable temporally resolved quantification of persistent organic pollutants andmetals in tooth biosamples. These exposure data will be used in both frequentist and Bayesian analyticframeworks to estimate effects of prenatal exposure in different time windows on continuous, categorical, andtrajectory ASD-related outcomes. Child genetic susceptibility will be incorporated into our analyses through thedevelopment and application of ASD- and exposure-specific genetic risk scores in order to maximize our abilityto detect risk due to prenatal POP and metal exposure. Then, because including ASD-ER subjects in ECHOwill also shift, and enrich the right tail of, dimensional ASD-related neurodevelopmental trait distributions in theECHO study population, we advocate for capitalizing on this by conducting a gene-environment wideinteraction study (GWIS) for ASD and related-outcomes in the full ECHO cohort and outline an approach forimplementing this. The unique features of ASD-ER (the enriched risk nature of the cohort combined with theavailability of already-completed deep neurodevelopmental phenotyping on all subjects and readily availablegenomic data plus a wide range of banked prenatal biosamples on subgroup) overlaid with the scale of thelarger ECHO effort, can combine to numerous opportunities for truly innovative science.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
