Epigenetic mechanisms act at the interface of genetic and environmental risk factors in autism. Project 2 is designed to investigate to focus on the epigenetic mark of DNA niethylation, as environmental toxins have been demonstrated to reduce global DNA methylation levels while methyl-donor nutrients can be protective. This project will make use primarily of human cord blood samples from the MARBLES study in order to test the hypothesis that epigenetic patterns laid down in eariy life that regulate synapse maturation and immune responses will be impaired in autism through interactions between genetic and environmental factors. The first aim is designed to perform a genome-wide analysis of DNA methylation and copy number variation and to study the association of differences in genetics and epigenetics with environmental exposures (from Project 1 and Core C) and nutrients. The second aim will investigate methylation of a specific gene locus, FOXP3, as an epigenetic marker of regulatory T cells and will make use of immunology expertise and existing participant samples from both MARBLES and CHARGE from Project 3. The third aim will test a multifactorial mechanistic model of transcription-induced epigenetic memory of perinatal gene x environment interactions at two specific loci, F0XP3 and FMR1, through interactions with Projects 3 and 4. Together these studies will increase understanding of the epigenetic interface between genetic and environmental risk factors in autism, leading to improved diagnosis, prevention, and therapies.