The influence of common genetic variation on brain overgrowth pathways

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Project Summary Many individuals with monogenic and idiopathic forms of autism spectrum disorder (ASD) exhibit larger brain volumes and a hyper-expansion of neocortical surface area early in life. An increase in the neural progenitor pool, present almost exclusively during fetal development, is a well-described mechanism that can lead to expansion of neocortical surface area. Numerous ASD-linked mutations affect genes involved in Wnt signaling, a pathway that regulates neural progenitor proliferation. In addition, common genetic variants near Wnt- pathway genes are associated with changes in cortical surface area in adults. Common variation plays a large role in ASD risk. Large and ever-growing genome-wide association consortia are identifying common variant loci associated with ASD risk. Based on these data, we hypothesize that both common and rare variants impact neocortical progenitor proliferation in fetal development by altering Wnt signaling, leading to post-natal cortical surface area hyper-expansion and increased ASD risk. The primary goal of this project is to identify common genetic variants influencing gene expression, Wnt signaling, and proliferation in response to Wnt modulators in primary human neuronal progenitor cell lines (phNPCs) from 107 genetically diverse donors. To accomplish this goal, we will first quantify inter-individual variability in transcriptional response to Wnt modulators. To modulate Wnt signaling, we will utilize two clinically relevant compounds (Valproic Acid, Lithium Chloride) as well as the most potent and selective Wnt activating compound available (CT99021). Next, we will quantify both canonical Wnt signaling, through a high-throughput luciferase assay, and proliferation, through a flow cytometry assay, in response to these Wnt modulators in this population of cells. Finally, we will perform a genetic association using the phenotypes we have collected on these cell lines to identify common variant loci associated with transcriptional, Wnt signaling and neural progenitor proliferation responses to Wnt modulators. We will determine if these same loci also influence risk for ASD and cortical surface area through co- localization techniques using existing genome-wide association studies. This study may allow us to understand the mechanism of action of ASD-associated genetic variation, implicating a cell-type and developmental process, which may lead to a more thorough understanding of ASD pathogenesis. In addition, as prenatal exposure to Valproic Acid is a known environmental risk factor for ASD, this study may identify genetic variants that impact responsiveness to Valproic Acid, allowing the prediction of adverse neurodevelopmental effects based on genotype.