Abstract
Sleep is a very rich phenotype and many aspects of sleep differ considerably in the population of healthy individuals (even when only a very narrow age range is considered). Interindividual variation in sleep timing (diurnal preference), sleep duration, sleep structure and the EEG in NREM sleep, and REM sleep and wakefulness, have all been shown to have a genetic basis. The response to challenges of sleep regulatory processes such as sleep deprivation and circadian misalignment has also been shown to vary between individuals. Some of the polymorphic variations in genes contributing to variation in sleep characteristics have now been identified. The most consistent variants include genes associated with circadian clock mechanisms (e.g., CLOCK, PER1-3, BHLHE41), adenosinergic (ADA) and monoaminergic neurotransmission (e.g., DAT1, DRD2, ADRB1), as well as transcription regulating pathways (e.g., PAX8, VRK2, MEIS1). For some of these genes, so far only associations with one aspect of sleep have been reported, for example, HCRTR2 and sleep timing. Variations in other genes have been shown to affect multiple aspects of sleep and wakefulness, as well as the response to sleep loss or pharmacological interventions. For example, PER3, ADA, and BDNF affect the EEG and performance during prolonged waking, whereas DAT1, DRD2, and ADORA2A modulate EEG and response to stimulants such as caffeine and modafinil. Apart from a few genes identified in familial pedigrees with extreme phenotypes (e.g., NPSR1 in a family with natural short sleep), the currently known polymorphic variations explain only a small part of the variation in healthy human sleep phenotypes. Deep phenotyping approaches covering the EEG in all three vigilance states, sleep structure and homeostatic aspects of sleep-wake regulation will be needed to provide further insights into intertwined and widespread consequences of genetic variants for healthy human sleep.