A Systems Approach Identifies Networks and Genes Linking Sleep and Stress: Implications for Neuropsychiatric Disorders

• A large, multiscale dataset to model interactions between stress and sleep in mice
• Reveals a dynamic genetic landscape and striatal gene networks for stress and sleep
• Highlights a mitochondria/synapse network linking stress and sleep
• Key regulators in sleep-stress networks implicated in neuropathology

SummarySleep dysfunction and stress susceptibility are comorbid complex traits that often precede and predispose patients to a variety of neuropsychiatric diseases. Here, we demonstrate multilevel organizations of genetic landscape, candidate genes, and molecular networks associated with 328 stress and sleep traits in a chronically stressed population of 338 (C57BL/6J × A/J) F2 mice. We constructed striatal gene co-expression networks, revealing functionally and cell-type-specific gene co-regulations important for stress and sleep. Using a composite ranking system, we identified network modules most relevant for 15 independent phenotypic categories, highlighting a mitochondria/synaptic module that links sleep and stress. The key network regulators of this module are overrepresented with genes implicated in neuropsychiatric diseases. Our work suggests that the interplay among sleep, stress, and neuropathology emerges from genetic influences on gene expression and their collective organization through complex molecular networks, providing a framework for interrogating the mechanisms underlying sleep, stress susceptibility, and related neuropsychiatric disorders.

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