A systems approach identifies networks and genes linking sleep and stress: implications for neuropsychiatric disorders.
Sleep 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.
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA.
Peng
P
Jiang
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Joseph R
JR
Scarpa
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA.
Karrie
K
Fitzpatrick
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Bojan
B
Losic
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA.
Vance D
VD
Gao
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Ke
K
Hao
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA.
Keith C
KC
Summa
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA.
He S
HS
Yang
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Bin
B
Zhang
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA.
Ravi
R
Allada
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA.
Martha H
MH
Vitaterna
Center for Sleep & Circadian Biology, Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA. Electronic address: fturek@northwestern.edu.
Fred W
FW
Turek
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: andrew.kasarskis@mssm.edu.
Andrew
A
Kasarskis
D000818:Animals; D001499:Bayes Theorem; D053263:Gene Regulatory Networks; D001523:Mental Disorders / Q000235:genetics / Q000473:pathology / Q000662:veterinary; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D040641:Quantitative Trait Loci; D012890:Sleep; D013315:Stress, Psychological / Q000235:genetics; D059467:Transcriptome
D008840:Microfilament Proteins