Genetics of sleep disorders

Publisher Summary

This chapter describes the genetic influence on normal sleep and its regulatory mechanism, and discusses recent clinical discoveries regarding the role of genetic factors in selected sleep disorders. The first sleep-related genes have been identified in monogenic disorders. Most of the sleep disorders have complex phenotypes. Using array technologies and performing genome-wide association studies and investigating thousands of patients and controls, common genetic susceptibility factors for sleep phenotypes are identified. Genome-wide sequencing with second-generation sequencers allows detecting rare genetic variants with a large effect on the phenotype. To explore the genetics of sleep disorders, epigenetic factors should be also considered that might explain the complexity of phenotypes. Sleep-related genes or mutations have been demonstrated in animal models, but, with the help of advanced molecular genetic approaches. Sleep genetics will soon expand into a search among human models and lead to pharmacogenomic development for individualized sleep medicine.

Introduction

In recent years, genetic approaches have became very popular in many fields of science. Finding causative genes specific for disorders and a variety of quantitative phenotypes is the hottest target in biomedical sciences, and such effort has also been made in the field of sleep research (Franken and Tafti, 2003, Lavie, 2005, Cirelli, 2009). One of the most successful findings in terms of sleep genetics so far is the discovery of the hypocretins/orexins, internal ligands of G-coupled orphan receptors in the hypothalamus. Hypocretins/orexins, when first discovered, were thought to function as appetite promoters (Sakurai et al., 1998), and it was then found that their impaired system initiates narcoleptic symptoms (Chemelli et al., 1999, Lin et al., 1999, Mieda and Yanagisawa, 2002, Sutcliffe and de Lecea, 2002, Sakurai, 2005, Nishino, 2007). However, as familial clustering had been observed in narcolepsy with a close association of human leukocyte antigens (e.g., HLA-DQB1 and HLA-DQA1), the discovery of gene products triggering or blocking narcolepsy was expected earlier (Peyron et al., 2000, Miyagawa et al., 2008). Thus, identifying a gene or its products responsible for sleep disorders will be difficult because of the complexity of these conditions.

However, there is an increasing demand for the discovery of genetic factors in sleep pathology (Taheri and Mignot, 2002, Dauvilliers et al., 2005, Dauvilliers and Tafti, 2008, Kimura and Winkelmann, 2007). It is known that several sleep problems can be inherited. Further, twin studies have demonstrated that sleep components are influenced significantly by genetic background. Thus, sleep regulation or dysregulation must be closely linked to genetic control. To prescreen a risk factor, find an adequate cure, or even classify the complexity of sleep phenotypes for further treatments, genetic information contributes to an in-depth understanding of the pathophysiology of major sleep disorders. Indeed, several mutations in particular genes are reported to be involved in certain sleep disorders. These “sleep-related” genes or mutations have mostly been demonstrated in animal models (Andretic et al., 2008), but, with the help of advanced molecular genetic approaches, sleep genetics will soon expand into a search among human models and lead to pharmacogenomic development for individualized sleep medicine.

In this chapter, we first describe the genetic influence on normal sleep and its regulatory mechanism, and then discuss recent clinical discoveries regarding the role of genetic factors in selected sleep disorders.