Environmental Epigenetics In Autism Spectrum Disorder

Abstract

The developing brain is highly sensitive to environmental exposures during the prenatal period. Evidence from neuroimaging, teratogen exposure case studies, and very early postnatal abnormalities demonstrate that the in utero exposure window is critical to risk of autism spectrum disorder (ASD). Genetic factors also contribute to ASD risk and large discovery efforts have identified important variants and structural changes. Studies of genetics or exposures in isolation to date explain a relatively small proportion of ASD risk. Epigenetics, including DNA methylation, represent a powerful gene-environment interaction mechanism. Prenatal exposures to toxicants such as cigarette smoke and heavy metals, or to nutritional supplements are associated with changes in DNA methylation measured in infants at birth. In an autism enriched-risk birth cohort we examine the roles of DNA methylation in multiple tissues and with environmental exposures. In the Early Autism Risk Longitudinal Investigation (EARLI), families with a child with ASD were recruited early in a subsequent pregnancy. Biological and exposure measures were obtained throughout pregnancy, including genome-wide DNA methylation measures in cord blood and placental tissues. Extensive neurophenotyping was performed until age three when ASD diagnoses were made. We show that the genomic locations of cord blood DNA methylation sites associated with ASD diagnosis are enriched for ASD risk genes. We further demonstrate that pregnancy exposures, such as to folic acid, result in global DNA methylation changes at birth, and this relationship is sensitive to maternal genotype. DNA methylation measures at birth may be ASD risk biomarkers, integrating genetic susceptibility and reflecting early life exposures. Environmental epigenetic epidemiological findings may have implications for ASD etiology.