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.