Genetics of the sleep-wake cycle and its disorders.

The sleep-wake cycle is under the control of the circadian clock. Recent advances in rhythm biology have identified molecular clocks and their key regulating genes. Circadian clock genes (Clock, Per) were first isolated in Drosophila, and their homologous counterparts have been found in mammals. Some of the circadian master genes have been shown to influence sleeping behavior. For instance, a point mutation in a human clock gene (Per2) was shown to produce the rare advanced sleep phase syndrome, whereas a functional polymorphism in Per3 is associated with the more frequent delayed sleep phase syndrome. Furthermore, a study examining the association between Clock gene polymorphisms and insomnia revealed a higher recurrence of initial, middle, and terminal insomnia in patients homozygous for the Clock genotype. Other genes have been shown to contribute to sleep pathologies. A point mutation in the prion protein gene appears to be the cause of fatal familial insomnia. A missense mutation has been found in the gene encoding the GABA-A beta 3 subunit in a patient with chronic insomnia. In both animal models and humans, a deficiency in the hypocretin/orexin system was proposed to be responsible for narcolepsy. Selective destruction of hypocretin neurons is the most probable culprit in humans. These findings suggest that the genetic contribution to sleep disorders and wake determinants is more important than originally thought. Beyond sleep, light/dark cycles and sleep deprivation appear also to be associated with eating habits, and epidemics of obesity have to be evaluated in the context of shortened sleep duration.