Current Biology 17, 613–618, April 3, 2007 ª2007 Elsevier Ltd All rights reserved
DOI 10.1016/j.cub.2007.01.073
Report
PER3 Polymorphism Predicts
Sleep Structure and Waking Performance
Antoine U. Viola,1 Simon N. Archer,1,2
Lynette M. James,1 John A. Groeger,3
June C.Y. Lo,3 Debra J. Skene,2
Malcolm von Schantz,1,2 and Derk-Jan Dijk1,2,*
1
Surrey Sleep Research Centre
2
Centre for Chronobiology
School of Biomedical and Molecular Sciences
3
Department of Psychology
School of Human Sciences
University of Surrey
Guildford GU2 7XH
United Kingdom
Summary
Circadian rhythmicity and sleep homeostasis interact
to regulate sleep-wake cycles [1–4], but the genetic basis of individual differences in sleep-wake regulation
remains largely unknown [5]. PERIOD genes are
thought to contribute to individual differences in sleep
timing by affecting circadian rhythmicity [6], but not
sleep homeostasis [7, 8]. We quantified the contribution of a variable-number tandem-repeat polymorphism in the coding region of the circadian clock
gene PERIOD3 (PER3) [9, 10] to sleep-wake regulation
in a prospective study, in which 24 healthy participants were selected only on the basis of their PER3 genotype. Homozygosity for the longer allele (PER35/5)
had a considerable effect on sleep structure, including
several markers of sleep homeostasis: slow-wave
sleep (SWS) and electroencephalogram (EEG) slowwave activity in non-rapid eye movement (non-REM)
sleep and theta and alpha activity during wakefulness
and REM sleep were all increased in PER35/5 compared
to PER34/4 individuals. In addition, the decrement of
cognitive performance in response to sleep loss was
significantly greater in the PER35/5 individuals. By
contrast, the circadian rhythms of melatonin, cortisol,
and peripheral PER3 mRNA expression were not
affected. The data show that this polymorphism in
PER3 predicts individual differences in the sleeploss-induced decrement in performance and that this
differential susceptibility may be mediated by its
effects on sleep homeostasis.
Results and Discussion
The coding region of the PERIOD3 (PER3) gene contains
a variable-number tandem-repeat (VNTR) polymorphism (insertion of nucleotides 3031–3084) in which a
motif encoding 18 amino acids is repeated either four
(PER34) or five times (PER35) [9]. These repeat units
contain a cluster of putative phosphorylation motifs
[10]. Retrospective studies have shown that this
*Correspondence: d.j.dijk@surrey.ac.uk
polymorphism is associated with diurnal preference
and delayed-sleep-phase syndrome (DSPS) [10–12].
Here we present the results of a prospective study in
which we investigated the functional consequences of
this polymorphism for sleep and circadian physiology
as well as waking performance. Subjects were selected
only on the basis of their genotype. Four hundred and
four men and women were genotyped in order to select
matched pairs of individuals who were homozygous for
the PER34 and PER35 alleles. These individuals then participated in a field study in which we characterized the
timing of their sleep-wake cycle. This field study was followed by an intensive physiological monitoring study, in
which circadian rhythms and homeostatic aspects of
sleep regulation and performance were quantified under
baseline conditions and subsequently during sleep loss.
Ten PER35/5 (4 women, 6 men; age 6 standard error of
the mean = 25.2 6 1.1 yr) and 14 PER34/4 (6 women, 8
men; 24.8 6 1.0 yr) healthy participants, closely matched
for age, sex, and ethnicity and without sleep complaints,
completed both the field and laboratory studies (see Table S1 in the Supplemental Data available online). Assessment of sleep timing by sleep diary and actigraphy
during the field study revealed no significant difference
in bed time (PER35/5, 01:03 6 0:32; PER34/4, 01:03 6
0:21; p > 0.05) or wake time (PER35/5, 07:57 6 0:28;
PER34/4, 08:41 6 0:21; p > 0.05) (Figure 1A). No major
difference was observed in reported sleep duration
(PER35/5, 06:55 6 0:19; PER34/4, 07:38 6 0:15; p >
0.05) or actigraphically assessed sleep duration
(PER35/5, 06:51 6 0:14; PER34/4, 07:19 6 0:12; p >
0.05). For assessment of the endogenous phase and
amplitude of circadian rhythms in the absence of the
confounding effects of light-dark and behavioral cycles,
participants underwent a constant-routine protocol, in
which they were kept awake in dim light (<5 lux) for approximately 40 hr in a semirecumbent posture [13, 14].
During this period, motor-activity levels did not differ between the genotypes and were near stable (Figure 1A),
indicating that the constant-routine protocol was
successful in eliminating the 24 hr activity cycle, which
masks endogenous circadian rhythms. PER3 mRNA
levels in total RNA extracted from peripheral blood
mononuclear cells exhibited a robust endogenous circadian rhythm with a peak value occurring at 06:42 6 01:04
in PER35/5 and 06:26 6 0:28 in PER34/4 (p > 0.05) (Figure 1B). This circadian rhythm is very similar to a previously reported profile [15]. The amplitude and mean
levels of PER3 mRNA were also not significantly different between the genotypes. The circadian rhythms of
plasma cortisol (Figure 1C) and melatonin (Figure 1D),
two hormonal rhythms driven by the circadian pacemaker in the suprachiasmatic nuclei of the hypothalamus, were also remarkably similar in the two genotypes.
The average peak value of cortisol occurred at 09:48 6
1:02 in PER35/5 and 9:00 6 00:27 in PER34/4. No difference was observed in cortisol amplitude. For the melatonin profile, the onset (PER35/5, 23:27 6 0:28; PER34/4,
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Figure 1. Endogenous Circadian Rhythms of Hormones and PER3
mRNA Levels Do Not Differ between PER35/5 and PER34/4 Homozygotes
(A) Shows the activity during the constant routine. Time courses of
(B) PER3 mRNA levels in total RNA extracted from blood mononuclear cells, (C) plasma cortisol concentration, and (D) plasma melatonin concentration are shown. All data are averaged across ten
PER35/5 (open symbols) and 14 PER34/4 (filled symbols) participants.
Error bars represent the standard error of the mean, and time represents local time.
23:45 6 0:21), offset (PER35/5, 08:44 6 0:24; PER34/4,
09:18 6 0:29), midpoint (PER35/5, 04:06 6 0:26; PER34/4,
04:31 6 0:24), and amplitude (PER35/5, 71.37 6 9.51
pg/ml; PER34/4, 72.78 6 10.82 pg/ml) did not differ between the genotypes (p > 0.05 in all cases).
Despite the absence of significant differences in the
timing and amplitude of these markers of central and peripheral circadian oscillators, the two genotypes differed
strikingly with respect to sleep propensity, electroencephalogram (EEG) during wakefulness and sleep, and
waking performance. Whereas during baseline, no differences were observed in rapid eye movement (REM)
sleep, stage 1 or 2 sleep, or total sleep time (see Table
S2), PER35/5 subjects fell asleep more readily than
PER34/4 subjects (sleep latency: PER35/5, 8.6 6 1.3 min;
PER34/4, 18.1 6 2.6 min; p < 0.005), indicating a greater
sleep propensity. Accordingly, these participants also
spent more time in slow-wave sleep (SWS) (PER35/5,
22.7% 6 1.6% of total sleep time; PER34/4, 15.7% 6
1.6% of total sleep time; p = 0.006), a well-established
marker of the homeostatic oscillator [16]. SWS is characterized by low-frequency, high-amplitude oscillations
in the EEG. Detailed analysis of the spectral composition
of the EEG during non-REM sleep (stages 1, 2, 3, and 4),
REM sleep, and wakefulness revealed that the effects of
the PER3 genotype on SWS were not caused by a general effect on the amplitude of the EEG. Instead, we
found that the effects of the PER3 genotype on the
EEG were specific to frequency and vigilance state.
Whereas during non-REM sleep (Figures 2A and 2B)
the largest differences were observed in the slowwave range, during REM sleep (Figures 2C and 2D)
and wakefulness (Figures 2E and 2F) the genotypedependent differences were located primarily in the
theta and alpha range. It is well established that slowwave activity (SWA) during non-REM sleep [17] and
EEG activity in the theta and alpha frequency range during wakefulness [18] and REM sleep [17, 19] track
homeostatic sleep pressure and sleepiness. Therefore,
the data imply that the PER3 polymorphism affects
sleep homeostasis in all three vigilance states.
This interpretation is strengthened by an analysis of
the effects of the PER3 polymorphism on the time
course of EEG activity during sleep. Baseline sleep of
PER35/5 participants was characterized by higher initial
values of SWA followed by a steeper decline (Figure 3A).
Alpha activity in REM sleep remained higher in PER35/5
throughout the sleep episode (Figure 3D). When the
sleep homeostatic system was challenged by sleep
deprivation, genotype-dependent differences in nonREM and REM sleep persisted. During recovery sleep,
the initial values of SWA during non-REM sleep (Figure 3B) and alpha activity in REM sleep throughout the
recovery episode (Figure 3E) were higher in PER35/5
(p < 0.05). As indexed by the duration of SWS and
REM, the response to sleep loss also differed between
the genotypes. In both genotypes, sleep deprivation
led to an increase in SWS (Figure 3C), but the associated
inhibition of REM sleep in the initial part of recovery
sleep was stronger in PER35/5 (Figure 3F).
As assessed in the constant-routine protocol, the increase in theta activity in the EEG during sustained
wakefulness differed noticeably between the genotypes. In PER35/5 individuals, it increased substantially
with time awake. By contrast, in the PER34/4 subjects,
no noticeable change was observed over time (Figure 4A). We also monitored the occurrence of slow
rolling eye movements (SEMs), an EEG-independent
marker of inattention and drowsiness [14]. Over the
course of the 40 hr of wakefulness, SEMs increased
more rapidly in PER35/5 than in PER34/4 homozygotes.
The largest differences between the genotypes were observed in the morning hours of the second day of sleep
deprivation (Figure 4B). The genotype-dependent difference in the response to sleep deprivation during the
biological night of these two markers of sleepiness
and inattention raises the possibility of a genetically
determined variability in susceptibility to the negative
effects of sleep deprivation on performance. We assessed various domains of waking performance (including working memory, attention, and psychomotor
PER3 Predicts Sleep and Waking Performance
615
Figure 2. EEG Power Spectra during nonREM Sleep, REM Sleep, and Wakefulness
Differ between PER35/5 and PER34/4 Homozygotes in a Vigilance-State and FrequencySpecific Manner
(A) Absolute EEG power-density spectra in
non-REM sleep (stages 1 to 4; frontal derivation) during baseline sleep.
(B) EEG power spectra in non-REM sleep of
PER35/5 participants during the first quarter
of the baseline sleep episode are expressed
relative the corresponding EEG power spectra in PER34/4 participants.
(C) Absolute EEG power-density spectra in
REM sleep (central derivation) during baseline sleep.
(D) EEG power spectra in REM sleep of
PER35/5 participants during baseline sleep
are expressed relative to the corresponding
EEG power spectra in PER34/4 participants.
(E) Absolute power spectra of EEG during
wakefulness (central derivation) in PER35/5
and PER34/4 homozygotes. EEG was recorded during dedicated 2 min sessions,
scheduled to occur every 2 hr during the constant routine.
(F) EEG power spectra during wakefulness in
PER35/5 participants are expressed relative
to the corresponding EEG power spectra in
PER34/4 participants.
In (A), (C), and (E), the error bars face upward
for PER35/5 and downward for PER34/4 participants. All values are plotted at the upper limit
of the 1 Hz frequency bands. * indicates a
significant difference between genotypes,
p < 0.05 (PER35/5 [open symbols]: n = 10 [all
panels], PER34/4 [filled symbols]: n = 13
[A, B, C, and D] or n = 14 [E and F]).
performance) during the extended period of wakefulness in a performance test battery consisting of verbal
and spatial 1-, 2-, and 3-back tests; a sustained-attention-to-response task; a paced-visual-serial-addition
task; a self-paced digit-symbol-substitution test; simple-reaction-time and serial-reaction-time tests; and a
motor-tracking task. The performance data were summarized by computation of a composite performance
score. Whereas during the first biological day of the constant-routine protocol performance was near stable in
both genotypes, the patterns dissociated when wakefulness was extended into the biological night (Figure 4C).
Most strikingly, PER35/5 homozygotes performed very
poorly during the hours after the melatonin midpoint.
The decrement in waking performance in the PER34/4
homozygotes was far less. These major differences in
performance between the two genotypes occurred during the late-night and early-morning hours, a time known
from both laboratory and field studies as the nadir of the
circadian timing system and during which performance
is poorest and sleep propensity at its peak [2]. This is
also the time at which many sleepiness-related accidents occur [20] and the greatest impairment is seen in
shift-work sleep disorders [21].
The PER3 5-repeat allele, which is the less frequent
one in most ethnic groups [22], has been associated
with extreme morning preference [10, 11], while the
4-repeat allele has been linked with DSPS in our previous study [10]. The primate-specific expansion of the
polymorphic region [23], its association with variation
in diurnal preference and DSPS [9–11], its potential impact on phosphorylation of the PER3 protein [10], and its
expression in hypothalamic and other brain areas implicated in sleep regulation [24, 25] led us to consider it as
a candidate for mediating some of the marked individual
differences in sleep-wake regulation. These individual
differences include the preferred timing of sleep-wake
cycles, the structure of sleep, EEG patterns during sleep
and wakefulness, and their response to sleep loss and
circadian-phase misalignment [20, 26–29].
Our results indicate that the PER3 polymorphism may
contribute to the marked individual differences in performance decrement during sleep loss [29]. The phenotypes that we found to be predicted by homozygosity
for the PER3 alleles are also reminiscent of some of
the classical phenotypes in human sleep research—
morning and evening types [30, 31], and short and
long sleepers [32]. Sleep in both morning types and
PER35/5 individuals is characterized by high initial values
of SWA, in particular when compared to evening types
who sleep at a similar circadian phase [30]. This is in
accordance with the previously reported association
between this PER3 polymorphism and diurnal preference in subjects selected from a larger population
sample [10]. Thus, this PER3 polymorphism appears to
contribute to the differences in sleep structure, but not
the differences in circadian timing [33], between morning and evening types.
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Figure 3. The Dynamics of EEG Slow-Wave Activity in non-REM Sleep, EEG Alpha Activity in REM Sleep, and the Sleep-Stage Response to Sleep
Loss Differ between PER35/5 and PER34/4 Homozygotes
(A, B, D, and E) Time courses of mean (6 standard error of the mean) slow-wave activity (SWA; 0.75–4.5 Hz) in non-REM sleep (stages 1–4) and
alpha activity (8–12 Hz) in REM sleep during the baseline and recovery sleep episodes for ten PER35/5 (open symbols) and 13 PER34/4 (filled symbols) participants. (* indicates a significant difference between genotypes, p < 0.05.)
(C) Slow-wave sleep (SWS) time and (F) REM sleep time expressed as a percentage of total sleep time (6 standard error of the mean) for baseline
and recovery sleep in PER35/5 (white bar) and PER34/4 (black bar) participants. For each participant, sleep-stage percentages during the baseline
sleep period were compared to the sleep-stage percentages for the same time period of recovery sleep. (* indicates a significant difference between genotypes or between baseline and recovery sleep, p < 0.05).
The sleep of habitual short sleepers is also characterized by high initial values of SWA and high levels of theta
activity in the EEG during wakefulness, very similar to
those reported here for PER35/5 individuals. The effect
of the PER3 polymorphism on SWA is of a comparable
magnitude to the effects of genetic variation in an already well-known key component of the homeostatic
regulation of sleep, the adenosine 2A receptor and
adenosine deaminase system [34].
In summary, this prospective study, in which subjects
were selected by genotype alone, demonstrates that the
PER3 VNTR polymorphism affects key markers of sleep
homeostasis, including sleep latency, SWS, theta activity in the waking EEG, and the decrement in waking performance in response to sleep loss. However, no significant effect on objective measures of sleep-timing and
circadian-rhythm parameters was observed. Within the
framework of the homeostatic and circadian regulation
of sleep and performance, these data imply that the
PER3 VNTR polymorphism affects the homeostatic aspect of sleep regulation. This is the first time that such
an effect has been demonstrated in humans and contrasts the limited animal data available for Per1 and
Per2 [7, 8]. However, in animal studies, other clock
genes, such as Clock, Cry1 and Cry2, NPAS2, DBP,
and BMAL1 have been shown to influence aspects of
the sleep and waking EEG as well as the response to
sleep loss [35–39], although effects on performance
have not previously been reported for any of these
genes. The independence of circadian and homeostatic
aspects of sleep regulation has been a mainstay of our
current models of sleep regulation [1, 40]. Nevertheless,
our data collected from humans, together with data from
mice, imply that this concept does not extend to the molecular level, and that some genes previously described
as clock genes perform noncircadian roles.
Conclusions
The effects of the PER3 polymorphism on SWS, SWA,
and the decrements of waking performance during the
biological night, as observed in this study, are significant
and substantial. This implies that this polymorphism
may be an important marker for individual differences
in sleep and susceptibility to sleep loss and circadianphase misalignment, which are major causes of health
problems and accidents in our society.
Supplemental Data
Supplemental Data include Experimental Procedures and two tables
and are available with this article online at: http://www.currentbiology.com/cgi/content/full/17/7/613/DC1/.
Acknowledgments
This research was supported by the Biotechnology and Biological
Sciences Research Council (BBSRC) (BSS/B/08523). We thank the
clinical and research team of the Clinical Research Centre and
Vanessa Kyriakopoulou, Alexander Garvin, Jayshan Carpen, Matt
Cooper, and Dr. Benita Middleton for their help.
Received: November 16, 2006
Revised: January 29, 2007
Accepted: January 29, 2007
Published online: March 8, 2007
PER3 Predicts Sleep and Waking Performance
617
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Figure 4. Deterioration of Waking Performance and Increase of
Theta EEG Activity and Slow Eye Movements during Sleep Deprivation Is Greater in PER35/5 Than PER34/4 Participants
Time course of (A) central EEG theta (5–8 Hz) activity during wakefulness, (B) incidence of slow eye movement (SEMs) (percentage of
30 s epochs containing at least one SEM), and (C) waking performance (composite performance score) are plotted relative to the
timing of the plasma melatonin rhythm (D) in ten PER35/5 (open symbols) and 14 PER34/4 (filled symbols) homozygotes. EEG theta activity, SEMs, and waking performance data were averaged per 2 hr
intervals, relative to the midpoint of the melatonin rhythm. (* indicates a significant difference between genotypes, p < 0.05; upper
abscissa indicates approximate wake duration.) Error bars represent the standard error of the mean.
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