Genetics of human circadian rhythms: using sequencing, novel phenotyping methods, and functional assays to move towards a deeper understanding of circadian mechanisms

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Project Summary/Abstract Circadian rhythms, our 24 daily biological rhythms, control nearly all our basic biological functions and are sensitive to the environment. Directing both environmental and pharmacological interventions at disrupted circadian rhythms has untapped potential to treat many conditions including cancer, psychiatric conditions, and cardiometabolic disorders. We first need, however, to understand the molecular mechanisms involved in circadian rhythms, particularly those linking the human circadian system to downstream disorders. Human genetics can provide insights important to address this gap in knowledge. The overall vision of this research program is understanding the underlying mechanisms of the human circadian system and its role in human health leading to integration of the temporal axis of our biology into preventative clinical care and treatment using a multifaceted and innovative approach. My research program spans from genetic discovery to functional follow-up to translational applications with the goals for the next five years to 1) use existing biobanks to identify individuals with extreme circadian behavior for rare variant studies resulting in identification of genes and pathways involved in circadian rhythms; 2) develop scalable human circadian phenotyping methods to enable detailed investigations of circadian behavior in large-scale populations well-powered for genetic studies; and 3) create novel circadian function follow-up cellular assays with the potential to interrogate the impact of gene knock out in a variety of environmental and genetic backgrounds and pair this novel functional screen with drosophila behavioral assays of circadian behavior. I am well-positioned to lead this research program as my background is in human genetics with experience in circadian rhythms and cellular screens for downstream functional assays with a proven-track record of success. As well, I have current and future collaborators positioned to contribute their expertise to this research program, with specific expertise in population genetic studies, circadian phenotyping in humans, and cellular circadian assays. Expected outcomes are: 1) genes, pathways, and cell types that contribute to circadian physiology particularly mechanisms beyond the core molecular circadian clock; 2) Tools for circadian risk prediction and stratification with utility in the workplace, educational environments, and clinical care; 3) Easy to implement and dynamic circadian phenotyping for research and clinical use across a broad range of study and care; and 4) Novel pharmaceutical targets for circadian rhythm disorders and causally linked disorders. These findings will allow for the development of novel therapeutics for rare circadian rhythms disorders and increase our understanding of the basic mechanisms of circadian biology in humans, and ultimately shed light on how circadian rhythm dysregulation predisposes to more common associated neuropsychiatric and cardiometabolic diseases.