Modeling autism-associated gene-by-environment interactions in human brain organoids

Abstract Genetic studies have been highly successful in identifying causal factors associated with autism spectrum disorders (ASD). However, current genetic associations do not completely explain liability for this complex disorder. Several environmental exposures, like air pollution, pesticide or heavy metal exposures, are associated with ASD through epidemiological studies. However, unlike genetic studies, these environmental epidemiological associations have inherent problems including that environmental factors are difficult to quantify, and confounding variables are prevalent. In addition, while epidemiological datasets can highlight risk factors for autism, developing new treatments requires an understanding of the cellular and molecular consequences of genetics and environmental exposures on brain cells. While both genetic and environmental risk factors for ASD have been identified, how genetic background accentuates or blunts response to environmental risk factors, termed gene x environment interactions (GxE), has not been well studied. Our group has pioneered the “GxE in a dish” approach to identify genetic variants modulating response to environmental toxicants using human neural cells including brain organoids where exposures can be tightly controlled. To identify how the combination of genetic variation and environmental exposures lead to risk for ASD, to identify cellular and molecular mechanisms mediating these effects, and to suggest treatment targets to reverse these, we will conduct “GxE in a dish” studies using cortical organoids to understand the cellular and molecular consequences of autism-associated environmental toxicants modulated by genetic variation. We will conduct acute and chronic exposures on cortical organoids derived from 115 unique participants to environmentally relevant concentrations of 7 toxicants and vehicle in cortical organoids, modeling exposures during pregnancy, and we will perform single cell RNA-seq (scRNA-seq) for each organoid. We will identify common genetic variants associated with differences in gene regulation in response to environmental exposures within each identified cell type. Then, we will determine the impact of exposure-sensitive genetic variants on ASD diagnosis, intellectual ability, and brain development. These analyses will highlight whether exposure-sensitive alleles accentuate ASD risk allele effects within specific cell types of the developing brain. Overall, our proposal will identify genetic variants exerting cell-type specific modulations on environmental exposures through a novel “GxE in a dish” design. Successful completion of these aims may uncover unexplained risk for ASD that cannot be accounted for by genetics or exposures in isolation.