Genetic and immunologic aspects of sleep and sleep disorders

Abstract

The study of genetics is providing new and exciting insights into the pathogenesis, diagnosis, and treatment of disease. Both normal sleep and several types of sleep disturbances have been found to have significant genetic influences, as have traits of normal sleep, such as those evident in EEG patterns and the circadian sleep-wake cycle. The circadian sleep-wake cycle is based on a complex feedback loop of genetic transcription over a 24-h cycle. Restless legs syndrome (RLS) and periodic limb movements in sleep (PLMS) have familial aggregation, and several genes have a strong association with them. Recent genome-wide association studies have identified single nucleotide polymorphisms linked to RLS/PLMS, although none has a definite functional correlation. Narcolepsy/cataplexy are associated with HLA DQB1*0602 and a T-cell receptor α locus, although functional correlations have not been evident. Obstructive sleep apnea is a complex disorder involving multiple traits, such as anatomy of the oropharynx, ventilatory control, and traits associated with obesity. Although there is clear evidence of familial aggregation in the obstructive sleep apnea syndrome, no specific gene or locus has been identified for it. Angiotensin-converting enzyme has been proposed as a risk variant, but evidence is weak. Fatal familial insomnia and advanced sleep phase syndrome are sleep disorders with a definite genetic basis.

Figure 1.

Power spectral analysis demonstrating the genetic influence on sleep EEG frequency power density. A, A female MZ twin pair with virtually identical EEG frequency power density. B, A single individual recorded on two different occasions. C, EEG frequency of a male MZ twin pair with virtually identical EEG power density. D, A male DZ twin pair with different EEG power spectrums. DZ = dizygous; MZ = monozygous. (Adapted with permission from Andretic et al.)

Figure 2.

Diagram of the molecular basis of the circadian sleep-wake cycle. The BMAL1 and CLOCK genes are transcribed to proteins BMAL1 and CLOCK, which combine to create a transcription factor BMAL1/CLOCK, which facilitates transcription of the PER and CRY proteins from their respective genes. PER and CRY form a dimer in the cytoplasm that gradually increases in concentration in the cytoplasm and reenters the nucleus, providing negative feedback. CK1ε CSNK1E facilitates degradation of PER. ROR1 and REV-ERBα regulate BMAL1. (Adapted with permission from Lowrey et al.)

Figure 3.

Genome-wide association study (GWAS) of restless legs syndrome (RLS). A Manhattan plot diagram of a GWAS demonstrating a common method of displaying data from a GWAS. The x axis shows various chromosome locations. The y axis displays the negative logarithm of the association P value. Each dot in the display represents different single nucleotide polymorphisms (SNPs), possibly linked to RLS. The stronger the association, the smaller the P value and the higher the negative logarithm. The higher the dot on the display, the more likely it is that the SNP is statistically different among those with the disease and those without it. In this display, 13 SNPs are significant and highlighted in bold (three SNPs on chromosome 15 are similar and appear as a single dot.) Gb = gigabases. (Adapted with permission from Winkelmann et al.)