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REM sleep. 43 This polymorphism is linked to a 2592C→T ins
polymorphism in the 3′-UTR of ADORA2A . The latter
may modulate protein expression. 51 Rétey and colleagues 43
observed that EEG spectral power in the range of approxi-
mately 7 to 10 Hz is higher in subjects with the 1083T→T
genotype than in individually-matched subjects with the
1083C→C genotype (see Fig. 15-2 ). Because the differ-
ence is not sleep or wakefulness specific, this polymor-
phism may modulate EEG generating mechanisms rather
than sleep-wake regulation. Moreover, the same genetic
variation in ADORA2A contributes to subjective and
objective responses to moderate caffeine intake on sleep. 52
The gene encoding the important catecholamine-
metabolizing enzyme catechol- O -methyltransferase
( COMT ) is located on human chromosome 22q11.2, in
proximity to ADORA2A . Human COMT contains a
common functional variation that alters the amino acid
sequence of COMT protein at codon 158 from valine (Val)
to methionine (Met). 53 Individuals homozygous for the Val
allele presumably show higher COMT activity and lower
dopaminergic signaling in prefrontal cortex than Met/Met
homozygotes. 54-56 Sleep variables and their response to
sleep deprivation do not differ between male carriers of
Val/Val and Met/Met genotypes. 57,57a In contrast, EEG
power in non-REM sleep, REM sleep, and wakefulness is
consistently lower in the upper-alpha (11 to 13 Hz) range
in Val/Val compared with Met/Met homozygotes. 58 This
difference is present before and after sleep deprivation, and
it persists after administration of the stimulant modafinil.
The data demonstrate that a functional variation of the
COMT gene is associated with robust interindividual dif-
ferences in the sleep EEG. This polymorphism profoundly
affects the efficacy of modafinil after sleep deprivation in
young healthy men. 57 Thus, two-time 100-mg modafinil
potently improved vigor and well-being, and maintained
baseline performance of executive functioning and vigilant
attention throughout 40 hours of prolonged wakefulness
in 10 Val/Val homozygotes, yet the same dosage was virtu-
ally ineffective in 12 Met/Met homozygotes. Interestingly,
an opposite relationship between Val158Met genotype of
COMT and measures of daytime sleepiness may be present
in patients suffering from narcolepsy (see Clinical Pearl ).
A point mutation at codon 178 (in rare cases also a muta-
tion at codon 200) of the prion protein gene (PRNP) has
been identified as the cause underlying the devastating
disease, fatal familial insomnia (FFI). 59 , 60 Interestingly,
although healthy relatives of FFI patients appear to have
normal sleep EEG, 61 the polymorphic codon 129 of the
PRNP gene may influence EEG activity during sleep. 62
Subjects with Met/Val genotype showed lower slow-wave
activity and higher spindle frequency activity than indi-
viduals with the Val/Val genotype, independent of codon
178.
How these alterations in sleep characteristics relate to
sleep-wake regulation and how they may lead to functional
consequences remains largely unexplored. The available
data, however, already indicate that the effects cross
boundaries between sleep and wakefulness, and between
homeostatic and circadian aspects of sleep-wake regula-
tion. For example, the polymorphisms in PER3, ADORA2A,
and COMT affect the EEG in non-REM sleep, REM
sleep, and wakefulness.
To investigate whether these changes reflect changes
in EEG generating mechanisms with or without a rela-
tionship to sleep regulatory processes requires these pro-
cesses to be challenged by, for example, sleep deprivation.
Comparing the response to sleep deprivation in PER3 5/5
individuals with that in PER3 4/4 individuals revealed that
the increase in theta activity in the EEG during wakeful-
ness was more rapid, and furthermore that the decline
of cognitive performance was more rapid. 42 This geno-
type-dependent differential susceptibility to the negative
effects of sleep loss on waking performance was particu-
larly pronounced in the second half of the circadian night
and on tasks of executive functioning. 63 One interpreta-
tion of these data is that the VNTR polymorphism in
PER3 affects the dynamics of the homeostatic process,
which then through its interaction with the circadian
regulation of performance leads to differential susceptibil-
ity to the negative effects of sleep loss. Indeed, an fMRI
study has shown that the changes in brain responses of
PER3 5/5 individuals to a working memory task during
sleep deprivation is very different from the changes in
PER3 4/4 individuals. Whereas PER3 4/4 individuals main-
tained activation and recruited new brain areas to the
task, brain responses were greatly diminished in PER3 5/5
individuals. 64 These laboratory data suggest that clock
and sleep genes could contribute to individual differences
in tolerance to shift work and jet lag, which are highly
prevalent in society.
CONCLUDING REMARKS
Sleep is a complex behavior, and any functional genetic
variation associated with changes in one of the many neu-
rotransmitter or neuromodulator systems can be expected
to affect sleep and the sleep EEG. Polymorphic variations
in a number of genes have now been shown to affect
several characteristics of sleep, and some of these genes
may indeed be involved in sleep regulatory processes. Elu-
cidating the signaling pathways that are affected will aid in
our understanding of individual differences in sleep-wake
behavior.
Acknowledgements
The authors' research is supported by Swiss National
Science Foundation, Zürich Center for Integrative Human
Physiology, and Novartis Foundation for Medical-Biolog-
ical Research (to HPL), and Biotechnology and Biological
Sciences Research Council, Wellcome Trust, the Air
Force Office of Scientific Research, and the Higher Edu-
cation Funding Council for England (to DJD).
GENETIC BASIS OF SLEEP-WAKE
REGULATION: INTERACTION
BETWEEN HOMEOSTATIC AND
CIRCADIAN SYSTEMS
Many of the traits and genes described here concern sleep-
wake characteristics as assessed under baseline conditions.
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