ABSTRACT It is increasingly apparent that both common and rare genetic variation influences the risk and severity of syndromic autism spectrum disorders (ASD). Among patients with highly penetrant ASD associated mutations there is often substantial heterogeneity in the severity of physical, behavioral, and cognitive deficits. However, precisely which regions of the human genome affect disease outcomes in the context of any high confidence ASD mutation are currently unknown. This critical gap in knowledge prevents the rational design of therapies that target underlying molecular and cellular deficiencies. Here, I will leverage genetically diverse iPSC lines to test the hypothesis that common genetic variation shapes the severity of hyperproliferation phenotypes caused by mutations in PTEN, a highly penetrant ASD associated gene. I will employ a novel pooled cell culture method, which allows rapid and efficient phenotyping of dozens of distinct lines in the same culture dish, to quantify the variation in hyperproliferation induced by PTEN haploinsufficiency. This will allow me to identify regions of the genome which modulate this ASD relevant phenotype, and test for the presence of sex specific genetic effects. I will then mechanistically validate associated loci with three distinct approaches. First, we will expand and validate our culture-based findings in patients with 1) idiopathic autism with brain overgrowth with longitudinal MRI and neurocognitive profiling, from whom these lines were generated, 2) ~600 deeply phenotyped patients with a variety of PTEN mutations and clinical presentations. Second, we will correlate our findings with those from other genome wide association studies to identify causal genes, and loci with shared genetic risk with other diseases. Third, we will validate associated loci in isogenic PTEN(+/-) lines, and test hypotheses aimed at the mechanisms by which genetic variants protect/exacerbate the effects of PTEN mutations. In all, the proposed studies will identify common genetic modifiers of phenotypic severity and patient outcomes in a genetically defined ASD subtype. To develop the expertise necessary for this cross-disciplinary project, I will undergo comprehensive training in bioinformatics, statistical genetics, and molecular neurodevelopment under the guidance of my primary mentor Jason Stein. I will also undergo supplemental training from my advisors in iPSC differentiation methods (Beltran), MRI image analysis (Piven/Styner), ASD pathogenesis (Piven/Zylka/Eng), and approaches to correlate genetic and clinical data (Stein/Piven/Eng). They will train me in the methods and principles required to successfully complete this project. This training will facilitate a successfully transition into my independent scientific career, where I will study genetic modifiers of neurodevelopmental disorders.