PER3 Polymorphism Predicts Sleep Structure and Waking Performance

Abstract

Circadian rhythmicity and sleep homeostasis interact to regulate sleep-wake cycles [1-4], but the genetic basis of individual differences in sleep-wake regulation remains largely unknown [5]. PERIOD genes are thought to contribute to individual differences in sleep timing by affecting circadian rhythmicity [6], but not sleep homeostasis [7, 8]. We quantified the contribution of a variable-number tandem-repeat polymorphism in the coding region of the circadian clock gene PERIOD3 (PER3) [9, 10] to sleep-wake regulation in a prospective study, in which 24 healthy participants were selected only on the basis of their PER3 genotype. Homozygosity for the longer allele (PER3(5/5)) had a considerable effect on sleep structure, including several markers of sleep homeostasis: slow-wave sleep (SWS) and electroencephalogram (EEG) slow-wave activity in non-rapid eye movement (non-REM) sleep and theta and alpha activity during wakefulness and REM sleep were all increased in PER3(5/5) compared to PER3(4/4) individuals. In addition, the decrement of cognitive performance in response to sleep loss was significantly greater in the PER3(5/5) individuals. By contrast, the circadian rhythms of melatonin, cortisol, and peripheral PER3 mRNA expression were not affected. The data show that this polymorphism in PER3 predicts individual differences in the sleep-loss-induced decrement in performance and that this differential susceptibility may be mediated by its effects on sleep homeostasis.

Genetic determination of sleep EEG profiles in healthy humans

“…Not only sleep architecture, but sleep EEG profiles are affected by this polymorphism. More specifically, the carriers of the PER3 5/5 genotype have higher EEG activity in the delta range (1-2 Hz) in NREM sleep and in the theta/alpha range (7-10 Hz) in REM sleep when compared to the the PER3 4/4 genotype (Viola et al, 2007). Moreover, the findings of another group suggested that the increase in slow-wave energy after acute sleep restriction is slightly elevated in adults carrying the …”

“…The repeated segments are translated into numerous potential phosphorylation sites and may alter posttranslational modification and stability of PER3 protein (Dijk and Archer, 2010). Viola et al (2007) observed that homozygous carriers of the long-repeat genotype (6 men, 4 women; mean age: 25.2 years) fall asleep more rapidly and showed more slow wave sleep than homozygous 4-repeat individuals (8 men, 6 women; mean age: 24.8 years). In addition, in recovery sleep after sleep deprivation, REM sleep is reduced in PER3 5/5 individuals compared to PER3 4/4 homozygotes.…”

Interindividual differences in circadian rhythmicity and sleep homeostasis in older people: effect of a PER3 polymorphism

“…In young people, the PER3 VNTR predicts diurnal preference such that those homozygous for the long repeat (PER3 5/5 ) prefer earlier wake-up and sleep time (Archer et al, 2003;Lázár et al, in press). Furthermore, in young people, the PER3 VNTR polymorphism also predicts interindividual differences in sleep structure and EEG power density in non-rapid eye movement (REM) sleep, REM sleep and wakefulness (Viola et al, 2007). PER3 5/5 individuals spent more time in SWS, have higher SWA in non-REM sleep, and a steeper dissipation of SWA during sleep episode as compared with those homozygous for the shorter, 4-repeat allele (PER3 4/4 ) (Viola et al, 2007).…”

“…Furthermore, in young people, the PER3 VNTR polymorphism also predicts interindividual differences in sleep structure and EEG power density in non-rapid eye movement (REM) sleep, REM sleep and wakefulness (Viola et al, 2007). PER3 5/5 individuals spent more time in SWS, have higher SWA in non-REM sleep, and a steeper dissipation of SWA during sleep episode as compared with those homozygous for the shorter, 4-repeat allele (PER3 4/4 ) (Viola et al, 2007). However, in young people, we did not observe significant differences between the genotypes with respect to the phase and amplitude of circadian markers, such as the hormones cortisol and melatonin and the clock genes PER3, BMAL1, and PER2 (Archer et al, 2008;Dijk and Archer, 2010;Viola et al, 2007).…”

Novel functions for Period 3 and Exo-rhodopsin in rhythmic transcription and melatonin biosynthesis within the zebrafish pineal organ

“…In contrast, per3 knock out mice have only a slight decrease in the period of their circadian clock [51]. In humans, certain polymorphisms in the per3 gene and misregulation of per3 expression have been associated with breast cancer, chronic myeloid leukemia, bipolar disorder, and the structure of the sleep/wake cycle [15,41,58,61,62].…”