title: Circadian gene variants influence sleep and the sleep electroencephalogram in humans.
abstract: The sleep electroencephalogram (EEG) is highly heritable in humans and yet little is known about the genetic basis of inter-individual differences in sleep architecture. The aim of this study was to identify associations between candidate circadian gene variants and the polysomnogram, recorded under highly controlled laboratory conditions during a baseline, overnight, 8 h sleep opportunity. A candidate gene approach was employed to analyze single-nucleotide polymorphisms from five circadian-related genes in a two-phase analysis of 84 healthy young adults (28 F; 23.21 ± 2.97 years) of European ancestry. A common variant in Period2 (PER2) was associated with 20 min less slow-wave sleep (SWS) in carriers of the minor allele than in noncarriers, representing a 22% reduction in SWS duration. Moreover, spectral analysis in a subset of participants (n = 37) showed the same PER2 polymorphism was associated with reduced EEG power density in the low delta range (0.25-1.0 Hz) during non-REM sleep and lower slow-wave activity (0.75-4.5 Hz) in the early part of the sleep episode. These results indicate the involvement of PER2 in the homeostatic process of sleep. Additionally, a rare variant in Melatonin Receptor 1B was associated with longer REM sleep latency, with minor allele carriers exhibiting an average of 65 min (87%) longer latency from sleep onset to REM sleep, compared to noncarriers. These findings suggest that circadian-related genes can modulate sleep architecture and the sleep EEG, including specific parameters previously implicated in the homeostatic regulation of sleep.
authors.affiliation: a Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology , Brigham and Women's Hospital , Boston , MA , USA.|b Division of Sleep Medicine , Harvard Medical School , Boston , MA , USA.|c Medical and Population Genetics , Broad Institute of Harvard and Massachusetts Institute of Technology , Cambridge , MA , USA.|d Department of Biobehavioral Health , Pennsylvania State University , University Park , PA , USA.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Chang
authors.affiliation: c Medical and Population Genetics , Broad Institute of Harvard and Massachusetts Institute of Technology , Cambridge , MA , USA.|e Department of Anesthesia, Critical Care and Pain Medicine and Center for Human Genetic Research , Massachusetts General Hospital , Boston , MA , USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Bjonnes
authors.affiliation: a Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology , Brigham and Women's Hospital , Boston , MA , USA.|b Division of Sleep Medicine , Harvard Medical School , Boston , MA , USA.|f Institute of Aerospace Medicine , German Aerospace Center , Cologne , Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Aeschbach
authors.affiliation: a Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology , Brigham and Women's Hospital , Boston , MA , USA.|b Division of Sleep Medicine , Harvard Medical School , Boston , MA , USA.|d Department of Biobehavioral Health , Pennsylvania State University , University Park , PA , USA.|g Department of Social and Behavioral Sciences , Harvard School of Public Health , Boston , MA , USA.
authors.forename: Orfeu M
authors.initials: OM
authors.lastname: Buxton
authors.affiliation: a Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology , Brigham and Women's Hospital , Boston , MA , USA.|b Division of Sleep Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Gooley
authors.affiliation: a Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology , Brigham and Women's Hospital , Boston , MA , USA.|b Division of Sleep Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Clare
authors.initials: C
authors.lastname: Anderson
authors.affiliation: a Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology , Brigham and Women's Hospital , Boston , MA , USA.|b Division of Sleep Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Eliza
authors.initials: E
authors.lastname: Van Reen
authors.affiliation: a Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology , Brigham and Women's Hospital , Boston , MA , USA.|b Division of Sleep Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Sean W
authors.initials: SW
authors.lastname: Cain
authors.affiliation: a Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology , Brigham and Women's Hospital , Boston , MA , USA.|b Division of Sleep Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Czeisler
authors.affiliation: a Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology , Brigham and Women's Hospital , Boston , MA , USA.|b Division of Sleep Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Jeanne F
authors.initials: JF
authors.lastname: Duffy
authors.affiliation: a Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology , Brigham and Women's Hospital , Boston , MA , USA.|b Division of Sleep Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lockley
authors.affiliation: a Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology , Brigham and Women's Hospital , Boston , MA , USA.|b Division of Sleep Medicine , Harvard Medical School , Boston , MA , USA.|h Oregon Institute of Occupational Health Sciences , Oregon Health & Science University , Portland , OR , USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Shea
authors.affiliation: a Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology , Brigham and Women's Hospital , Boston , MA , USA.|b Division of Sleep Medicine , Harvard Medical School , Boston , MA , USA.
authors.forename: Frank A J L
authors.initials: FA
authors.lastname: Scheer
authors.affiliation: a Division of Sleep and Circadian Disorders, Department of Medicine and Department of Neurology , Brigham and Women's Hospital , Boston , MA , USA.|b Division of Sleep Medicine , Harvard Medical School , Boston , MA , USA.|c Medical and Population Genetics , Broad Institute of Harvard and Massachusetts Institute of Technology , Cambridge , MA , USA.|e Department of Anesthesia, Critical Care and Pain Medicine and Center for Human Genetic Research , Massachusetts General Hospital , Boston , MA , USA.
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
mesh_terms: D000293:Adolescent; D000328:Adult; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology*; D004569:Electroencephalography / Q000379:methods; D005260:Female; D006706:Homeostasis / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007206:Individuality; D008297:Male; D056950:Period Circadian Proteins / Q000235:genetics*; D017286:Polysomnography / Q000379:methods; D012890:Sleep / Q000502:physiology*; D014851:Wakefulness / Q000235:genetics / Q000502:physiology*; D055815:Young Adult
chemical_list: C421902:PER2 protein, human; D056950:Period Circadian Proteins
keywords: Circadian genes; sleep EEG; slow-wave activity; slow-wave sleep