Sleep and circadian rhythms play critical roles in the maintenance of physical and mental health, with disturbances in these domains associated with major public health consequences. Despite the abundance of epidemiological evidence linking sleep and circadian traits to diverse pathologies, little is known about the genetic factors that underlie these traits. Sleep and circadian traits, such as insomnia and chronotype, are highly heritable and aggregate in families, suggesting a substantial proportion of risk is due to genetics. Progress has been made in identifying risk variants for these traits using genome-wide association studies (GWAS). However, GWAS results principally reside in non-coding regions of the genome and rarely pinpoint the precise location of the actual effector genes. Mounting evidence is indicating that simply attributing GWAS signals to the genes encoded in the closest genomic regions is not always accurate. As such, GWAS alone is primarily beneficial to signal discovery, not functional gene discovery. The difficulty in elucidating the actual effector genes for human GWAS signals is a significant barrier to identifying novel molecular regulators of sleep. Despite wide-ranging tools utilizing model systems and in vitro approaches to conduct such functional analyses, as well as computational methods to implicate causal variants, these approaches are underutilized in the sleep and circadian domain. This proposal seeks to fill this critical knowledge gap by employing a team science approach, bringing together expertise in the genomics of sleep and circadian rhythms that spans humans, model systems, and computational biology, while simultaneously leveraging large existing datasets for genetic discovery.
In Aim 1, we will leverage existing biobank data for discovery of risk variants for insomnia and chronotype. This will be followed, in Aim 2, by examination via a battery of spatial genomic analyses of these loci using IPSC-derived neuro progenitor cells to identify causal variants. Finally, we will determine which genes have functional relevance using Drosophila as a model system. Our global hypothesis is that genomic variation is strongly associated with the behavioral manifestation of insomnia and chronotype and that our cutting-edge molecular approaches will elucidate the causal variants and the corresponding effector genes at these loci.
We aim to translate genetic information into meaningful benefits for patient care by uncovering the correct functional context of GWAS identified genomic variants involved in these traits and understanding how they operate in this context.

Public Health Relevance

Sleep and circadian rhythms play critical roles in the maintenance of physical and mental health, with disturbances in these domains associated with major public health consequences. Leveraging a combination of genetic, functional and animal model approaches, we aim to characterize the genomic underpinnings of this trait. This study will fill a critical need to uncover their biologic mechanisms underlying these traits in order to improve diagnostic, preventive and treatment approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL143790-02
Application #
9769865
Study Section
Cancer, Heart, and Sleep Epidemiology A Study Section (CHSA)
Program Officer
Laposky, Aaron D
Project Start
2018-09-01
Project End
2022-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Stahl, Bethany A; Peco, Emilie; Davla, Sejal et al. (2018) The Taurine Transporter Eaat2 Functions in Ensheathing Glia to Modulate Sleep and Metabolic Rate. Curr Biol 28:3700-3708.e4
Zandawala, Meet; Yurgel, Maria E; Texada, Michael J et al. (2018) Modulation of Drosophila post-feeding physiology and behavior by the neuropeptide leucokinin. PLoS Genet 14:e1007767
Duboué, Erik R; Borowsky, Richard L; Keene, Alex C (2012) ?-adrenergic signaling regulates evolutionarily derived sleep loss in the Mexican cavefish. Brain Behav Evol 80:233-43