Idiopathic hypersomnia (IH) is a poorly understood disorder characterized by excessive daytime sleepiness despite normal nighttime sleep, often accompanied by difficulty awakening, unrefreshing sleep, and cognitive impairment. Once thought to be present in <1% of the population, recent work indicates a far greater prevalence, with underdiagnosis exacerbated by a limited understanding of this disorder. IH patients commonly report poor management of symptoms and impaired quality of life, and treatments are not based on disease etiology. Twin studies show that daytime sleepiness is between 37-48% heritable and family history of excessive sleepiness, IH, or other hypersomnia disorders is present in ~1/3 of IH patients. Genome-wide association studies (GWAS) of hypersomnia traits have identified 24 genome- wide significant SNPs specifically associated with increased sleep propensity. Here, we propose a comprehensive approach to identify effector genes for hypersomnia-related traits, using “variant to gene mapping to in vivo validation” that will intersect GWAS data with ATAC-seq and high-resolution promoter- focused Capture C neuronal datasets derived from human induced pluripotent stem cells (iPSCs) to identify potential effector genes. We will rapidly validate identified candidates in an established Drosophila model of sleep and extend findings into zebrafish to test for behavioral relevance in a vertebrate system. Using approaches described in this proposal, we have already strongly implicated a gene, vertebrate CADM2, as associated with hypersomnia-like phenotypes across species with loss of function. In Aim 1, we will use a comprehensive combination of TAD-wise analysis of genome wide significant sleep propensity loci and “3D Genomics” approaches in key cell types to implicate additional candidate effector genes harbored in the sub-threshold P-value zones of the existing GWAS datasets. In Aim 2, we will use Drosophila to determine the mechanism through which loss of CADM2 (functional homolog in fly, beat-Ia) affects the function of key arousal circuits in the brain. In parallel, we will screen identified candidate genes for relevance to excessive sleepiness in vivo in flies using an RNAi-based approach. In Aim 3, we will rigorously examine sleep phenotypes in Cadm2b knockout zebrafish and prioritize other candidate genes for vertebrate using a rapid CRISPR approach pipeline. This project will identify novel genetic variants and the corresponding effector genes that contribute to hypersomnia-related traits, thereby shedding light on the biological pathways that influence the development of the traits. Study results will have fundamental implications for novel approaches to the diagnosis, prevention, and treatment of IH.