Whole genome dissection of genetic mechanisms that underlie the phenotypic spectrum of autism It is recognized that the genetic etiology of Autism Spectrum Disorder (ASD) is multifactorial, with contributions from multiple factors including de novo mutations, rare inherited variants, polygenic risk scores (PRS) and sex. Genetic studies have identified >100 ASD susceptibility genes. However, studies have each been carried out one modality at a time (GWAS, exome or genome). Consequently, there are major gaps in our understanding of the genetic mechanisms underlying ASD. For instance, the heritability of ASD explained has not been systematically characterized for all forms of rare and common variant risk, including structural variant (SVs) and tandem repeats (TRs). Non-additive effects of rare and common variants have not been systematically explored. Furthermore, it is not understood how rare and common variants, in genes and neurodevelopmental pathways, influence ASD symptom domains and ultimately converge to a diagnosis of ASD. Recent studies from our labs (PMID: 35654974, 33442040) have shown that multiple factors act in combination in the individual to determine risk for ASD, and each genetic factor has distinct phenotypic correlates. These results highlight knowledge that can be gained from an integrated analysis of genomic and phenotypic datasets in ASD families. With a vast increase in sample size, we have sufficient power to address these questions in the following aims (1) Complete assembly of genomic and phenotypic data on 62,328 ASD families (N = 204,428 subjects) and perform a whole genome analysis of the heritability explained by common and rare SNVs, SVs, and TRs; (2) Investigate novel genetic mechanisms that could explain missing heritability, including gene x gene and gene x sex, interactions; and (3) Dissect the genetic effects of molecular and cellular pathways on cognitive traits. An integrated analysis of variant types across a range of frequencies could set a new bar for the heritability of ASD explained, could yield clues to the nature of the unexplained, and could provide mechanistic basis insights into the effects of genes on cognition