Variant-to-gene mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as a regulator of sleep

Abstract

Genome-wide association studies (GWAS) in humans have identified loci robustly associated with several heritable diseases or traits, yet little is known about the functional roles of the underlying causal variants in regulating sleep duration or quality. We applied an ATAC-seq/promoter focused Capture C strategy in human iPSC-derived neural progenitors to carry out a “variant-to-gene” mapping campaign that identified 88 candidate sleep effector genes connected to relevant GWAS signals. To functionally validate the role of the implicated effector genes in sleep regulation, we performed a neuron-specific RNA interference screen in the fruit fly, Drosophila melanogaster , followed by validation in zebrafish. This approach identified a number of genes that regulate sleep including a critical role for glycosylphosphatidylinositol (GPI)–anchor biosynthesis. These results provide the first physical variant-to-gene mapping of human sleep genes followed by a model organism–based prioritization, revealing a conserved role for GPI-anchor biosynthesis in sleep regulation.

Pleiotropic effects of a high confidence Autism Spectrum Disorder gene, arid1b, on zebrafish sleep

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“…Behavioral asymmetries were long thought to be unique to humans, yet we now know that paw, hand, foot, and eye preferences are observed in nearly all bilateral species, and neural asymmetries likely underlie these behaviors [4][5][6][7][8] , which potentially provide a powerful behavioral to functional connection. Cross-species comparisons are a powerful approach to assess not only the conservation of behaviors but also to define how behavioral responses change according to the environment, behavioral adaptation, or genetic heterogeneity [9][10][11][12] . For many asymmetric behaviors, like handedness or eye preferences, genetics only partially instructs these behaviors [13][14][15] , suggesting that external forces such as organismal experience may also be a contributing factor.…”