Elucidating the Interplay of Genes and Environment in Autism Using Genomic and Exposure Data from Large Populations

Elucidating the Interplay of Genes and Environment in Autism Using Genomic and Exposure Data from Large Populations Abstract Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition influenced by both genetic and environmental factors. While rare and common genetic variants have identified over 100 ASD-associated genes and copy number variants (CNVs), the mechanisms through which environmental exposures modify genetic susceptibility remain poorly understood. A major barrier to progress has been insufficient sample size to rigorously investigate gene-environment interactions (G×E). To address this gap, we have assembled a combined dataset of 2.7 million individuals with paired genetic, environmental, and clinical data across multiple cohorts. This study will apply innovative causal inference frameworks to disentangle direct environmental effects from gene-environment correlation, identify genetic modifiers of environmental exposures, and develop predictive models integrating genetic, environmental, and clinical data. In Aim 1, we will investigate prenatal exposures and early-life environmental factors in two deeply phenotyped cohorts (ABCD, HBCD) with genome-wide genetic data, neurodevelopmental assessments, neuroimaging, and EEG. In Aim 2, we will examine G×E effects in neonatal intensive care using whole genome sequencing and perinatal electronic health record (EHR) data from the BeginNGS consortium. In Aim 3, we will conduct large-scale meta-analyses of these studies with biobanks (Regeneron, UK Biobank, All of Us, Estonian Biobank) and the SPARK ASD family cohort to identify G×E interactions, and to elucidate causal pathways through which environmental exposures contribute to ASD. The proposed study will generate novel insights into modifiable environmental risk factors and their interaction with genetic susceptibility to ASD, providing a foundation for targeted prevention and personalized intervention strategies.