PERIOD3, circadian phenotypes, and sleep homeostasis.
Circadian rhythmicity and sleep homeostasis contribute to sleep phenotypes and sleep-wake disorders, some of the genetic determinants of which are emerging. Approximately 10% of the population are homozygous for the 5-repeat allele (PER3(5/5)) of a variable number tandem repeat polymorphism in the clock gene PERIOD3 (PER3). We review recent data on the effects of this polymorphism on sleep-wake regulation. PER3(5/5) are more likely to show morning preference, whereas homozygosity for the four-repeat allele (PER3(4/4)) associates with evening preferences. The association between sleep timing and the circadian rhythms of melatonin and PER3 RNA in leukocytes is stronger in PER3(5/5) than in PER3(4/4). EEG alpha activity in REM sleep, theta/alpha activity during wakefulness and slow wave activity in NREM sleep are elevated in PER3(5/5). PER3(5/5) show a greater cognitive decline, and a greater reduction in fMRI-assessed brain responses to an executive task, in response to total sleep deprivation. These effects are most pronounced during the late circadian night/early morning hours, i.e., approximately 0-4h after the crest of the melatonin rhythm. We interpret the effects of the PER3 polymorphism within the context of a conceptual model in which higher homeostatic sleep pressure in PER3(5/5) through feedback onto the circadian pacemaker modulates the amplitude of diurnal variation in performance. These findings highlight the interrelatedness of circadian rhythmicity and sleep homeostasis.
Dijk
Derk-Jan
DJ
Surrey Sleep Research Centre, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XP, UK. d.j.dijk@surrey.ac.uk
Archer
Simon N
SN
D000483:Alleles; D000818:Animals; D001921:Brain / Q000502:physiology; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology; D004569:Electroencephalography; D005838:Genotype; D006706:Homeostasis / Q000235:genetics* / Q000502:physiology; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008550:Melatonin / Q000097:blood; D018598:Minisatellite Repeats / Q000235:genetics; D056950:Period Circadian Proteins / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D012890:Sleep / Q000235:genetics* / Q000502:physiology; D012895:Sleep, REM / Q000235:genetics / Q000502:physiology; D014851:Wakefulness / Q000235:genetics / Q000502:physiology
C512644:PER3 protein, human; D056950:Period Circadian Proteins; D008550:Melatonin