Drosophila Modeling of Insomnia-Associated Genes Reveals Diverse Underlying Sleep Phenotypes

Insomnia is a prevalent sleep disorder with highly heterogenous manifestations. While data-driven approaches to insomnia subtyping have revealed potential differences between proposed insomnia subtypes and their impacts on overall health, little is known about the genetic factors that underly and differentiate these potential insomnia subtypes. We utilize a human-genetics driven approach to Drosophila modeling to identify the range of sleep traits regulated by insomnia-associated genes. Modeling pan-neuronal loss of Drosophila orthologs of a set of insomnia genes reveals a broad range of sleep phenotypes. Through systematic characterization of traits related to sleep quantity, timing, and quality, we identify genetic factors that co-regulate aspects of the insomnia-associated phenotypic landscape. Out of the 75 insomnia-associated genes identified, only 1/3 had at least one Drosophila ortholog that regulated overall sleep quantity. In contrast, 1/3 of the insomnia-associated genes had at least one Drosophila ortholog that regulated either sleep timing or sleep quality, without impacting sleep quantity. Together this work, in Drosophila , provides support for a genetic influence on the differences between insomnia subtypes.