Better understanding of the etiologic roles of family history, prenatal environmental factors, and potential biologic mechanisms, such as epigenetic changes, in autism spectrum disorders (ASD) are research priorities identified in the Autism Coordinating Committee 2011 Strategic Plan for Autism Spectrum Disorder Research, but rapid progress is hampered by the challenges of acquiring relevant data in large epidemiologic samples. The goals of the current proposal are to examine: (1) fundamental controversies concerning familial and environmental contributions to risk for ASD; (2) transmission of risk across generations; (3) investigate pregnancy-related environmental factors in ASD, and (4) the potential role of epigenetic changes in those factors. We will build on an existing research network leveraging established population-based epidemiologic resources from seven countries (USA-California, Australia, Denmark, Finland, Israel, Norway, Sweden) that include individual-level perinatal medical, and demographic information and archived biospecimens. Study data will be based on over 4.5 million births (1998-2007), over 20,000 cases of ASD, and family linkages over three generations (grandparents, parents/aunts/uncles, siblings/cousins). Using this unparalleled resource, we propose a novel multigenerational perspective in ASD risk across four integrated aims: Aim 1: Model familial recurrence risk and the contributions of shared environmental factors to ASD liability, building on advanced modeling approaches using extended family relations. Aim 2: Determine if parental components of ASD risk are transmitted across generations, specifically, advancing parental/grandparental age and parental/grandparental immigration of minority groups. Aim 3: Examine ASD risk from prenatal exposure to medications with potential adverse neurodevelopmental effects: a) valproate; b) 2-adrenergic receptor agonists; c) selective serotonin reuptake inhibitors; or d) antibiotics that impede folate metabolism, i.e., sulfonamides and Trimethoprim. Aim 4: Using genomic DNA extracted from archived neonatal blood-spot samples, examine epigenetic changes in children with ASD exposed prenatally to the maternal medications in the previous aim. The resource established by the MINERvA Network will allow more accurate and precise determination of the contributions of familial and environmental factors to the etiology of autism, in particular if medications for maternal chronic and acute conditions prescribed in pregnancy contribute to ASD risk, and whether epigenetic processes underlie a biological abnormality linked to autism. From a public health perspective the study will accelerate the characterization of high risk groups, modifiable risk factors and the elucidation of mechanisms in autism etiology that could ultimately contribute to preventive measures or interventions and treatments.