Genetics of circadian rhythms and mood spectrum disorders
Mood spectrum disorders (bipolar disorder, recurrent depressive disorder and seasonal affective disorder) are accompanied by circadian deregulations, which can occur during acute mood episodes as well as during euthymic periods, and are particularly common among bipolar patients in remission. This suggests that altered circadian rhythms may be biological markers of these disorders. Rhythm dysfunctions have been observed in mood disorder patients by using actigraphic measures and by assessing social metric rhythms, diurnal preferences and melatonin secretion. Since many of these markers are heritable and therefore driven by clock genes, these genes may represent susceptibility factors for mood spectrum disorders. Indeed, several genetic association studies have suggested that certain circadian gene variants play a role in susceptibility to these disorders. Such connections to circadian genes such as CLOCK, ARNTL1, NPAS2, PER3 and NR1D1 have been repeatedly demonstrated for bipolar disorders, and to a lesser extent for recurrent depressive disorders and seasonal affective disorders. The study of circadian phenotypes and circadian genes in mood spectrum disorders represents a major field of research that may yet reveal the pathophysiological determinants of these disorders.
Genetics of circadian rhythms and mood
⁎, V. Milhiet
, F. Bellivier
, M. Leboyer
Inserm, U955, Créteil, 94000, France
Université Paris Est, Faculté de médecine, Créteil, 94000, France
AP-HP, Hôpital H. Mondor - A. Chenevier, Service hospitalier, Créteil, 94000, France
Fondation Fondamental, Créteil, 94000, France
Received 26 May 2011; received in revised form 7 July 2011; accepted 13 July 2011
Mood spectrum disorders (bipolar disorder, recurrent depressive disorder and seasonal affective
disorder) are accompanied by circadian deregulations, which can occur during acute mood
episodes as well as during euthymic periods, and are particularly common among bipolar patients
in remission. This suggests that altered circadian rhythms may be biological markers of these
disorders. Rhythm dysfunctions have been observed in mood disorder patients by using
actigraphic measures and by assessing social metric rhythms, diurnal preferences and melatonin
secretion. Since many of these markers are heritable and therefore driven by clock genes, these
genes may represent susceptibility factors for mood spectrum disorders. Indeed, several genetic
association studies have suggested that certain circadian gene variants play a role in
susceptibility to these disorders. Such connections to circadian genes such as CLOCK, ARNTL1,
NPAS2, PER3 and NR1D1 have been repeatedly demonstrated for bipolar disorders, and to a lesser
extent for recurrent depressive disorders and seasonal affective disorders. The study of circadian
phenotypes and circadian genes in mood spectrum disorders represents a major field of research
that may yet reveal the pathophysiological determinants of these disorders.
© 2011 Elsevier B.V. and ECNP. All rights reserved.
⁎Corresponding author at: Pôle de psychiatrie, Hôpital Albert
Chenevier, 40 rue de Mesly, 94010 CRETEIL cedex, France. Tel.: + 33
1 49 81 32 90; fax: +33 1 49 81 30 99.
E-mail address: email@example.com (B. Etain).
Mood disorders are complex and multifactorial disorders
caused by genetic, environmental, physiological and psycho-
logical factors. Such illnesses include bipolar disorders,
recurrent depressive disorders (or unipolar depression) and
seasonal affective disorders (SAD; also called ‘winter
0924-977X/$ - see front matter © 2011 Elsevier B.V. and ECNP. All rights reserved.
European Neuropsychopharmacology (2011) 21, S676–S682
depression’). Altered circadian rhythms (changes in mood,
appetite, sleep and energy level) have been observed during
episodes of mania and depression as well as in periods of
remission (in particular for bipolar disorders). Circadian
rhythm abnormalities have therefore attracted considerable
attention as possible biomarkers of these disorders. The
association between circadian parameters and mood deregu-
lation is also strongly connected to the ‘social zeitgeber
theory’(Grandin et al., 2006). “Zeitgeber”is the German word
for “time-giver”and refers to environmental or external time
cues that are likely to entrain circadian rhythms in humans.
The ‘social zeitgeber theory’describes a mechanism that links
life stress and mood regulation. According to this theory,
stressors in daily life disrupt social routines, thus affecting
biological circadian rhythms that in turn lead to mood episodes
amongst vulnerable individuals. In this article, we will review
the current knowledge of abnormal circadian rhythms in mood
spectrum disorders and show that these diseases are associ-
ated with vulnerabilities in the internal circadian clock
machinery and that the genes involved in circadian rhythm
regulation (circadian genes and melatonergic genes) are
possible susceptibility factors for these disorders.
English article selection was performed in Medline, ISI database,
EMBASE, PsychInfo, Centre for Reviews and Dissemination and
Databases of Thomson Reuters in February 2011. The key terms
used for psychiatric conditions were mood disorder, bipolar
disorder, depression, unipolar depression, major depressive disor-
der, winter depression and seasonal affective disorder. The key
terms used for circadian rhythms were circadian rhythms, circadian
markers, chronotype, circadian gene, clock gene and melatonin.
They were cross-referenced separately with each other. The search
criteria were presence of word in any field of the article. The
authors also searched in the reference list of each included paper for
additional studies not found in the first step.
3. Circadian system: molecular functioning
Circadian rhythms include all physiological processes (biolog-
ical and behavioral) that display a period of around 24 hours.
The main circadian pacemaker is located in the suprachias-
matic nuclei (SCN). The molecular mechanisms in the SCN
consist of networks of transcriptional–translational feedback
loops that give a rhythmic expression pattern to clock genes
(Takahashi et al., 2008). The intrinsic circadian rhythm is
slightly longer than 24 h without environmental cues (free-
running rhythm). Indeed, the endogenous oscillations can
adapt to a daily synchronization led by environmental time
signals (entrainment). The day–night cycle is the principal
synchronization signal, which involves specialized retinal
ganglion cells that project through the retinohypothalamic
tract to SCN. The SCN then transfer neuronal and neuroendo-
crine information through output pathways to regulate
rhythmic clock-controlled gene expression which controls
many rhythmic physiological functions, such as the sleep–
wake cycle, feeding behavior, body thermoregulation, hor-
mone release and metabolic regulation (Takahashi et al.,
2008). The second main circadian pacemaker is the pineal
gland, which synthesizes melatonin. Melatonin secretion is
regulated by the environmental light/dark cycle via the SCN: it
increases before bedtime, stays high during the nocturnal sleep
period, decreases quickly around wake time, and is almost
undetectable during daytime due to the inhibition of melatonin
secretion by light (Pandi-Perumal et al., 2006). Melatonin
the time of year (seasonal variation). Melatonin levels can be
assessed by measuring it in the blood or saliva and by measuring
its urinary metabolite, 6-sulfatoxymelatonin. The most com-
monly used circadian melatonin phase marker is the dim light
melatonin onset (DLMO) (Benloucif et al., 2008). Several
arguments suggest that circadian systems and monoamine
neurotransmission closely interact. Indeed, in mice or rats,
monoaminergic neurotransmitter machinery (synthesis, catab-
olism and receptors) implicated in mood regulation exhibit
circadian transcription and traduction variations. It has been
mainly observed for serotonergic (Barassin et al., 2002;
Malek et al., 2004), dopaminergic (Akhisaroglu et al., 2005;
Castaneda et al., 2004) and noradrenergic (Aston-Jones et al.,
4. Circadian abnormalities as markers in mood
Many measures of circadian rhythms exist, consisting mainly
of sleep diaries, chronotypes, actigraphic parameters and
melatonin secretion profiles. One sleep diary widely used in
the study of mood disorders is the Social Rhythm Metric
(Monk et al., 1990). It assesses the effects of daily social and
occupational rhythms on sleep quantity and quality. It has
been reported that bipolar patients exhibited less regular
lifestyles than those of healthy controls (Sylvia et al., 2009).
The regularity of daily activities was found to be lower in
people at risk for bipolar disorders (hypomanic personality)
than in normal controls, and their sleep duration was more
variable (Meyer and Maier, 2006). Poor social rhythm
regularitywas also observed ina sample of 414 undergraduate
students diagnosed with bipolar spectrum (cyclothymia or
bipolar disorder type II) and appeared to be a significant
predictor for the onset of major depressive, hypomanic and
manic episodes in a prospective follow-up nearly three years
later (Shen et al., 2008). Bipolar and recurrent depressive
disorders seem to share this lack of external synchronization,
which includes the disruption of social rhythms leading to the
onset of affective episodes (primarily manic onsets) (Malkoff-
Schwartz et al., 1998, 2000).
Chronotypes can be assessed through self-report question-
naires, such as the Horne-Östberg morningness–eveningness
questionnaire (MEQ) (Horne and Ostberg, 1976)orthe
Composite Scale of Morningness (CSM) (Smith et al., 1989),
which are used to characterize subjects as either ‘morning or
evening types’. These questionnaires are very useful because
the MEQ and CSM scores correlate strongly with various
endogenous phase markers of the circadian clock, such as
body temperature, salivary melatonin secretion or cortisol
awakening response. In bipolar disorders, three recent studies
have reported that patients were more likely than control
subjects to be ‘evening types’(Ahn et al., 2008; Mansour et al.,
2005; Wood et al., 2009). Several recent studies demonstrated
that eveningness was also associated with more frequent
depressive states (Hasler et al., 2010; Hidalgo et al., 2009; Kim
et al., 2010; Kitamura et al., 2010). Diurnal preference for
S677Genetics of circadian rhythms and mood spectrum disorders
evening may enhance susceptibility to affective symptoms,
both depressive and manic. Evening preference has also been
observed in SAD (Elmore et al., 1993), although this was not
confirmed in two more recent studies (Johansson et al., 2003;
Natale et al., 2005).
Actigraphy studies of circadian rhythms in euthymic
patients with bipolar disorders suggest that, compared to
controls, these patients have greater variability in their
sleep/wake patterns measured across days (Jones et al.,
2005), longer sleep duration and lower daily activity (Harvey,
2008; Harvey et al., 2005; Millar et al., 2004; Salvatore et
al., 2008). High-risk subjects (unaffected first-degree
relatives of bipolar patients) exhibited greater variability
in sleep characteristics (duration, fragmentation, and
efficiency), shorter sleep duration, later and more variable
bedtimes, and lower relative amplitude of activity patterns
compared to a normal control group (Ankers and Jones,
2009). Subnormal actigraphic patterns have also been
observed in SAD, such as lower daylight activity, attenuated
amplitude of the sleep–wake cycle, lower sleep efficiency
and phase delay (Teicher et al., 1997; Winkler et al., 2005).
It has been suggested that bipolar patients secrete
abnormal levels of melatonin and are hypersensitive to light.
For example, in a sample of euthymic patients and in a sample
of acutely ill patients, melatonin levels in response to light
were twofold lower than those of controls (Lewy et al., 1985;
Nathan et al., 1999). Nevertheless, this association remains
controversial (Lam et al., 1990; Whalley et al., 1991). Some
authors have proposed that abnormal overnight serum
melatonin levels may be a promising biomarker for bipolar
disorders, which is observed independently of the illness state
(Kennedy et al., 1996). Some bipolar patients showed
significantly lower melatonin levels on the light night, at
baseline andfollowing light exposure; and a later peak timefor
melatonin on the dark night (Nurnberger et al., 2000).
Depressed patients do not differ from controls in their mean
level of melatonin, but their peak nocturnal melatonin
secretion occurs later and their urinary 6-sulfatoxymelatonin
concentrations are higher in the morning. These characteris-
tics suggest that melatonin production is phase-shifted in
major depression (Crasson et al., 2004). Melatonin has been
proposed to be critically involved in the development of SAD
(Pandi-Perumal et al., 2006) because the morning decreases in
the plasma melatonin levels of these individuals relative to
controls are delayed (Pacchierotti et al., 2001). Altogether,
abnormalities in melatonin secretion patterns (with respect to
amplitude and period of secretion, but not total amount) may
be plausible biomarkers of mood disorders and relevant during
episodes of illness or remission (Pacchierotti et al., 2001).
The main studies investigating these circadian markers
are briefly presented in Table 1.
Most circadian variables are heritable, such as diurnal
preference (morningness/eveningness) (Barclay et al., 2010;
Klei et al., 2005; Koskenvuo et al., 2007; Vink et al., 2001),
certain sleep characteristics (Dauvilliers et al., 2005)and
melatonin-related markers (Hallam et al., 2006). This herita-
bility suggests that these markers of circadian deregulation
are, at least inpart, driven by genetic factors. Thus, genes that
encode proteins involved in the regulation of circadian
rhythms are of crucial interest since they represent putative
susceptibility factors for mood disorders and may prevent
circadian rhythms from properly adapting to external cues.
5. Circadian gene polymorphisms and mood
Many results of classical genetic association studies have
implicated circadian genes in the genetic susceptibility to
mood spectrum disorders. Table 2 shows that independent
studies have suggested associations between bipolar disorders
and several circadian genes such as CLOCK,NPAS2,ARNTL1,
PER3 or NR1D1. Multi-locus interactions among BHLHB2-
CSNK1ε-CLOCK (Shi et al., 2008) and copy number variations
within the GSK3beta gene (Lachman et al., 2007) have also
been reported. Moreover, a convergent functional genomics
approach, which integrates data from animal models of gene
expression with data from human genetic linkage/association
studies and with data obtained from human tissues (postmor-
tem brain and blood studies), has suggested that several genes
Table 1 Some evidence for associations between circadian markers and mood spectrum disorder.
Euthymic BD ⁎UD/Major depression⁎⁎ SAD ⁎⁎
(Ashman et al., 1999; Bullock et al., in press;
Sylvia et al., 2009)
(Haynes et al., 2005)-
Eveningness (Ahn et al., 2008; Mansour et al., 2005;
Wood et al., 2009)
Association with depressivity (Hasler
et al., 2010; Hidalgo et al., 2009; Kim
et al., 2010; Kitamura et al., 2010)
(Elmore et al., 1993)
not replicated in
(Johansson et al., 2003;
Natale et al., 2005)
(Harvey, 2008; Harvey et al., 2005; Jones et
al., 2005; Millar et al., 2004; Salvatore et al.,
(Volkers et al., 2003)(Teicher et al., 1997;
Winkler et al., 2005)
(Kennedy et al., 1996; Lewy et al., 1985;
Nathan et al., 1999; Nurnberger et al., 2000)
not confirmed in (Lam et al., 1990; Whalley
et al., 1991)
(Buckley and Schatzberg, 2010;
Crasson et al., 2004)
(Dahl et al., 1993)
BD: bipolar disorder, UD: unipolar disorder, SAD: seasonal affective disorder.
⁎: for BD: most parameters are trait-markers.
⁎⁎: for UD/Major depression: most parameters are state-markers.
S678 B. Etain et al.
involved in circadian rhythms regulation pathways (such as
ARNTL1 or GSK3beta) are primary candidates for genes linked
to bipolar disorders (Le-Niculescu et al., 2009). Unipolar
disorders have also been associated to circadian genes,
including the promoter region of AANAT (arylalkylamine N-
acetyltransferase) (Soria et al., 2010a), CRY1, NPAS2 (Soria et
al., 2010b), ASMT (Acetyl Serotonin Methyl Transferase, the
rate-limiting enzyme for melatonin synthesis) (Galecki et al.,
Table 2 Studies reporting suggestive associations between circadian genes and mood spectrum disorders BD: bipolar disorder,
UD: unipolar disorder, SAD: seasonal affective disorder.
Gene OMIM nomenclature Studies reporting suggestive associations
BD UD Major
CLOCK CIRCADIAN LOCOMOTOR OUTPUT
(Kripke et al., 2009; Lee et al., 2010;
Shi et al., 2008; Soria et al., 2010b)
(Soria et al.,
NPAS2 NEURONAL PAS DOMAIN PROTEIN 2 (Kripke et al., 2009; Mansour et al.,
2009; Soria et al., 2010b)
(Soria et al.,
(Johansson et al.,
2003; Partonen et
ARNTL1 ARYL HYDROCARBON RECEPTOR
NUCLEAR TRANSLOCATOR-LIKE 1
(Mansour et al., 2006, 2009;
Nievergelt et al., 2006; Soria et al.,
(Soria et al.,
2010b; Utge et
(Partonen et al.,
ARNTL2 ARYL HYDROCARBON RECEPTOR
NUCLEAR TRANSLOCATOR-LIKE 2
(Soria et al., 2010b)(Soria et al.,
PER1 PERIOD HOMOLOG 1 (DROSOPHILA) (Kripke et al., 2009)
PER2 PERIOD HOMOLOG 2 (DROSOPHILA) (Kripke et al., 2009)(Soria et al.,
(Partonen et al.,
PER3 PERIOD HOMOLOG 3 (DROSOPHILA) (Mansour et al., 2006; Nievergelt et
al., 2006; Soria et al., 2010b)
(Soria et al.,
CRY1 CRYPTOCHROME 1 (Soria et al., 2010b)(Soria et al.,
CRY2 CRYPTOCHROME 2 (Mansour et al., 2009)(Lavebratt et al.,
TIMELESS TIMELESS HOMOLOG (DROSOPHILA) (Mansour et al., 2006)(Utge et al.,
NR1D1 NUCLEAR RECEPTOR SUBFAMILY 1,
GROUP D, MEMBER 1
(Kishi et al., 2008; Kripke et al., 2009;
Severino et al., 2009)⁎
(Soria et al.,
RORA RAR-RELATED ORPHAN RECEPTOR A (Soria et al., 2010b)(Utge et al.,
RORB RAR-RELATED ORPHAN RECEPTOR B (Mansour et al., 2009; McGrath et al.,
CSNK1δCASEINE KINASE I DELTA (Kripke et al., 2009)
CSNK1εCASEINE KINASE I EPSILON (Mansour et al., 2009; Shi et al., 2008;
Soria et al., 2010b)
(Utge et al.,
GSK3βGLYCOGEN SYNTHASE KINASE 3-BETA (Szczepankiewicz et al., 2006)⁎
DBP D SITE OF ALBUMIN PROMOTER-
(Soria et al.,
BHLHB2 BASIC HELIX-LOOP-HELIX DOMAIN
CONTAINING, CLASS B, 2
(Shi et al., 2008)
BHLHB3 BASIC HELIX-LOOP-HELIX DOMAIN
CONTAINING, CLASS B, 3
(Soria et al., 2010b)
(Galecki et al.,
MTNR1B MELATONIN RECEPTOR 1B (Galecka et al.,
AANAT ARYLALKYLAMINE N-
(Soria et al.,
PPARGC1B PEROXISOME PROLIFERATOR-
COACTIVATOR 1, BETA
(Kripke et al., 2009)
⁎: association observed only for females with bipolar disorders (Kishi et al., 2009; Szczepankiewicz et al., 2006).
S679Genetics of circadian rhythms and mood spectrum disorders
2010), TIMELESS (Utge et al., 2010), NR1D1 (Kishi et al., 2008),
CRY2 (Lavebratt et al., 2010); and the melatonin receptor 2
gene (Galecka et al., in press)(seeTable 2). Finally, a genome-
wide association study for the depression scale of the Revised
NEO Personality Inventory found an association between trait
depression and the circadian gene, RORA (Terracciano et al.,
2010). Genetic association studies have also demonstrated the
potential implication of several circadian genes (PER2, ARNTL
and NPAS2) in SAD (Johansson et al., 2003; Partonen et al.,
To date, etiological determinants of mood spectrum disorders
remain poorly understood. The growingnumber of reports that
have investigated the relationships between these disorders
and circadian genes, chronotypes and circadian physiological
processes strongly suggest that chronobiology may help to
clarify the underpinning mechanisms of mood disorders.
Consistent results have emerged, which suggest that circadian
gene variants may influence the susceptibility to mood
spectrum disorders. Some of these genes have been found to
be commonly associated with bipolar disorders, recurrent
depression and winter depression, whereas other genes have
been associated with specific disorders. Harvey has recently
proposed a model for bipolar disorders, which integrates
genetic susceptibility, sleep and circadian functioning, neu-
rotransmitter output and mood deregulation, and which may
also explain mood spectrum disorders (Harvey, 2008). In this
model, some genetic variants of candidate genes (mainly
circadian ones) predispose individuals to being relatively less
able to properly adapt their circadian rhythms to their
environment and, to being prone to sleep disturbances.
Since circadian and neurotransmission systems are tightly
connected, circadian and/or sleep-related abnormalities may
impact the functioning of the dopamine and serotonin
circuitry, which in turn affects mood regulation. A vicious
cycle is then created in which mood deregulation affects sleep
quality and quantity, which thus disturbs rhythm stability.
Further investigations of circadian phenotypes and circadian
genes in mood spectrum disorders represent major avenues of
research for comprehending their pathophysiological
Role of the funding source
The supplement that this article appears in was produced with an
educational grant from Servier. The authors received a fee from
Servier for their work on this supplement.
Authors BE, VM and FB managed the literature searches and wrote
the manuscript. Author ML supervised the manuscript drafting. All
authors contributed to and have approved the final manuscript.
Conflict of interest
BE and ML received honoraria from Servier Pharmaceutical Company.
VM and FB declare that they have no conflicts of interest.
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