Circadian Rhythms, Sleep Deprivation, and Human Performance - Progress in Molecular Biology and Translational Science - page 168

5.2. Genetics of individual differences in chronotype and
circadian rhythms
Morningness-eveningness is estimated to be about 50% heritable. 129 The
genetic basis of morningness-eveningness in the general population has been
investigated by targeting several core circadian genes, producing inconsistent
results. 130 For example, the 3111C allele of the CLOCK gene 5 0 -UTR region
has been associated with eveningness and delayed sleep timing in some stud-
ies 131-133 but not others. 98,134-138 Similarly, the variable number tandem
repeat (VNTR) polymorphism in PERIOD3 ( PER3 ),anothercoreclock
gene, has been linked to diurnal preference, but not consistently, 135,139-148
thereby underscoring the need for further investigation on this topic. Both
the 111G polymorphism in the 5 0 -untranslated region of PERIOD2 ( PER2 )
and theT2434Cpolymorphismof PERIOD1 havebeenassociatedwithmorn-
ing preference 149,150 though not consistently. 134 Since morningness-
eveningness represents a continuum, it is likely this trait is polygenic, influenced
by several genes, eachcontributing to thedeterminationof circadianphasepref-
erence. Thus, further studies investigating other clock genes, as well as replica-
tion of the PER and CLOCK findings, are needed to establish precisely the
molecular components of behavioral circadian phase preference.
Interindividual differences in morningness-eveningness are believed to
manifest into extreme cases classified as primary circadian rhythm sleep dis-
orders (CRSDs), with altered phase relationships of the biological clock to
the light-dark cycle, including alterations in sleep timing. 151,152 Thus,
extreme eveningness is thought to result in CRSD, delayed sleep phase type
(usually referred to as a disorder and abbreviated as DSPD 152 ) , while extreme
morningness can manifest as CRSD, advanced sleep phase type (usually
referred to as a disorder and abbreviated as ASPD). 151,152 The extent to
which these phase-displacement disorders reflect differences in endogenous
circadian period, amplitude, coupling, entrainment, or other aspects of clock
neurobiology has been the focus of recent research.
The genetic basis of DSPD and ASPD related to phenotypic chronotype
has been investigated in recent years, both demonstrating links to core clock
genes. 130,153,154 DSPD, the most common CRSD in the general population,
is characterized by an inability to fall asleep at the desired and “normal” time
of day; the average onset of sleep in DSPD occurs in the early morning
(0300-0600 h), and the average wake-up time occurs in the late morning
to early afternoon (1100-1400 h). 152 DSPD also may be characterized by
a longer than normal tau (e.g., 25 h). 155 The VNTR polymorphism in

PER3 is associated with DSPD in large sample studies, 139,140,142 and the