title: Identification of causal genes, networks, and transcriptional regulators of REM sleep and wake.
abstract: OBJECTIVE
  Sleep-wake traits are well-known to be under substantial genetic control, but the specific genes and gene networks underlying primary sleep-wake traits have largely eluded identification using conventional approaches, especially in mammals. Thus, the aim of this study was to use systems genetics and statistical approaches to uncover the genetic networks underlying 2 primary sleep traits in the mouse: 24-h duration of REM sleep and wake.
  
  
  METHODS
  Genome-wide RNA expression data from 3 tissues (anterior cortex, hypothalamus, thalamus/midbrain) were used in conjunction with high-density genotyping to identify candidate causal genes and networks mediating the effects of 2 QTL regulating the 24-h duration of REM sleep and one regulating the 24-h duration of wake.
  
  
  METHODS
  Basic sleep research laboratory.
  
  
  METHODS
  Male [C57BL/6J × (BALB/cByJ × C57BL/6J*) F1] N(2) mice (n = 283).
  
  
  METHODS
  None.
  
  
  RESULTS
  The genetic variation of a mouse N2 mapping cross was leveraged against sleep-state phenotypic variation as well as quantitative gene expression measurement in key brain regions using integrative genomics approaches to uncover multiple causal sleep-state regulatory genes, including several surprising novel candidates, which interact as components of networks that modulate REM sleep and wake. In particular, it was discovered that a core network module, consisting of 20 genes, involved in the regulation of REM sleep duration is conserved across the cortex, hypothalamus, and thalamus. A novel application of a formal causal inference test was also used to identify those genes directly regulating sleep via control of expression.
  
  
  CONCLUSIONS
  Systems genetics approaches reveal novel candidate genes, complex networks and specific transcriptional regulators of REM sleep and wake duration in mammals.
authors: Sage Bionetworks, Seattle, WA, USA.
authors: Joshua
authors: J
authors: Millstein
authors: Christopher J
authors: CJ
authors: Winrow
authors: Andrew
authors: A
authors: Kasarskis
authors: Joseph R
authors: JR
authors: Owens
authors: Lili
authors: L
authors: Zhou
authors: Keith C
authors: KC
authors: Summa
authors: Karrie
authors: K
authors: Fitzpatrick
authors: Bin
authors: B
authors: Zhang
authors: Martha H
authors: MH
authors: Vitaterna
authors: Eric E
authors: EE
authors: Schadt
authors: John J
authors: JJ
authors: Renger
authors: Fred W
authors: FW
authors: Turek
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C / Q000235:genetics; D008810:Mice, Inbred C57BL / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D012895:Sleep, REM / Q000235:genetics*; D013788:Thalamus / Q000378:metabolism; D014851:Wakefulness / Q000235:genetics*