The role of GPI-anchor biosynthesis in sleep regulation

PROJECT SUMMARY Sleep disorders such as insomnia are common and have major public health consequences. Enormous resources have been invested in human sleep genomics, with data from several million individuals yielding genome-wide association study (GWAS) loci associated with sleep disorders. However, these associated genetic variants principally reside in non-coding regions of the genome and rarely pinpoint the precise location of the actual effector genes. Mounting evidence suggests that simply attributing GWAS signals to the genes within the closest genomic proximity is insufficient to identify the genetic variation associated with phenotypic changes. As such, GWAS results alone are limited to signal discovery, with only indirect implications for functional gene discovery. Here, we seek to address major barriers to further understanding sleep GWAS signals by applying genomic, computational, and behavioral approaches to study the basis of human sleep. We have developed a pipeline for functionally validating sleep genes from human GWAS, and used this to identify GPI-anchor biosynthesis as a critical regulator of sleep in animal models, as well as humans. In this application we will identify targets of this pathway in fruit flies, and the underlying mechanism of their impact on sleep centers in the brain. We will use then apply variant-to-gene mapping in human progenitor cells (NPCs) to identify how genetic variation associated with sleep-regulating genes impact their function. We will also characterize the impact of variation in insomnia risk genes by conducting in-depth human phenotyping of individuals harboring rare variants with predicted loss of function. Our global hypothesis is that genetic variation in the GPI-anchor biosynthesis pathway, and genes encoding for GPI-anchor proteins are critical regulators of sleep. Our cutting-edge molecular genomic approaches will elucidate the causal variants and the corresponding effector genes at these loci.