Circadian rhythms regulate human behavior and physiology within the 24hr day. Dysregulation of those rhythms are associated with sleep disorders, cognitive and physical performance, cancer, and chronic disease, however, little is known about the link between human circadian rhythms and health and physiology. We will identify novel genetic factors for circadian rhythms by sequencing extreme circadian rhythm disorder patients. For this purpose, we are assembling a new cohort study. Circadian rhythm disorders are inherited sleep disorders of the circadian system, which present as extremely shifted or irregular sleep timing and current treatments are limited, difficult to implement, and ineffective. Initial family-based genetic studies of circadian rhythm disorders implicated mutations in genes involved in the core molecular circadian clock (PER2, PER3, CSNK1D). In our study, we will extend the interrogation of circadian rhythm disorder causative mutations beyond the few family-based studies by recruiting a new cohort of circadian disorder patients, with the hypothesis that patients with extreme circadian rhythm disorders harbor rare loss-of-function mutations in core components of the circadian clock. We will test this by establishing a novel at-home testing based extreme circadian disorder cohort and identifying new genes for circadian rhythm disorders by sequencing and analyzing the exome of circadian rhythm disorder patients.
Ultimately, this work will identify new causal genetic factors for circadian rhythm disorders and elucidate biological pathways underlying circadian regulation. These findings will benefit circadian disorder patients by allowing for the development of novel therapeutics for rare circadian rhythms disorders, increasing our understanding of the basic mechanisms of circadian biology in humans, and ultimately shedding light on how circadian rhythm dysregulation predisposes to associated chronic diseases.