Philip Gehrman - US grants

PROJECT SUMMARY 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.

Project Summary Insomnia is among the most commonly experienced symptoms and is associated with significant distress and impairment. The assessment of insomnia is reliant on patient self-report, which is often influenced by a number of factors other than illness severity, complicating accurate diagnosis and treatment. Further, subtypes of insomnia may exist based on the presence or absence of short sleep duration. Identification of a biological ?signature? of insomnia that could facilitate assessment and subtyping would dramatically improve symptom management. Metabolic biomarkers have significant promise for meeting this need. Individuals with insomnia demonstrate metabolic hyperarousal compared to good sleepers. Acute disruption of sleep in the laboratory impacts the metabolome but the extent to which these findings extrapolate to chronic sleep disturbance or insufficient sleep is unknown. Our own data indicate there is a clear metabolic signature that differentiates patients with insomnia from good sleepers. The objective of this study is therefore to investigate the effects of chronic insomnia and insufficient sleep on metabolic profiles. In order to test this hypothesis we will conduct in- depth phenotyping of sleep and metabolism in 100 subjects who are in one of four groups (n=25 per group): 1) patients with insomnia and objective short sleep (<6 hours) on actigraphy; 2) patients with insomnia without objective short sleep (>6 hours); 3) habitual short sleepers (<6 hours) without evidence of insomnia; and 4) good sleepers. Home overnight polysomnography and actigraphy will be used to rule out comorbid sleep disordered breathing and confirm the presence of insomnia. All subjects will participate in a four-day inpatient protocol in the Center for Human Phenomic Science. Food intake will be provided in hourly isocaloric snacks to control for meal-induced shifts in metabolism. The first two days will be used to acclimate subjects to the environment and meals. On the morning of day 3 they will have an indwelling catheter placed for blood sampling every two hours for 48 hours with overnight polysomnography each night. During this time lighting levels will be kept constantly dim (<250 lux) to minimize the effects of light exposure on circadian rhythms. Metabolomics analysis of serum samples will be carried out using NMR and mass spectroscopy. Blood samples will also be used for melatonin and cortisol assays as standard markers of circadian rhythmicity. The global hypothesis that motivates this proposal is that chronic insomnia, insufficient sleep, and their combination are associated with distinct profiles of systemic metabolic dysregulation.