This grant supports the continuation of an investigation of prenatal and newborn biologic markers for autism previously funded by NIH. This project, known as the Early Markers for Autism (EMA) Study, is the first large, population-based case-control study to utilize these very early biologic specimens to elucidate underlying causes of autism. Preliminary results from the first funding cycle indicate that the mid-pregnancy immune profile of mothers of children with autism spectrum disorders (ASD) is dysregulated in comparison to mothers of control children. The goal of the new study is to investigate further the role of prenatal and newborn immunologic factors, genetic susceptibility factors, environmental exposures, and the interplay of genes with environment, by evaluating stored prenatal (maternal) and newborn blood specimens for children with autism, children with mental retardation (MR) but not autism, and population controls. This study will utilize a much larger case-control cohort among a new sample of 1,200 mother-baby pairs (400 ASD, 400 MR, 400 GP controls), with an added family-based component that includes 60 siblings of ASD cases and 60 siblings of MR controls. Specimens will be analyzed for markers of immune system function (cytokines, chemokines, antibodies to fetal brain), environmental exposures (organochlorine pesticides, PCBs, and PBDEs), and candidate single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) regulating immune function, xenobiotic metabolism and detoxification, and maternal-fetal transport. This large sample size will ensure sufficient statistical power for the examination of relatively rare exposures, phenotypic subgroups of ASD, and ethnic subgroups. Results of this study will contribute to identifying factors that increase the risk for autism and may lead to eventual prevention of autism and related disorders.