Diversity of Human Clock Genotypes and Consequences - Progress in Molecular Biology and Translational Science - page 54

Furthermore, this variation correlates with differences in experiencing seasonal
variation of energy levels. 25
BMAL1 may contribute to fertility. An intronic polymorphism has been
shown to link to the number of pregnancies and miscarriages. 25 This is in
agreement with studies in Bmal1 -null mutant mice, which demonstrates that
Bmal1 is necessary for fertility. 26,27 Loss of Bmal1 in male mice results in
reduced testosterone production, 26 while in female mice, Bmal1 deficiency
leads to impaired growth and development of the reproductive system,
reduced ovulation rate, and failure of fertilized oocytes to implant. 27
Lastly, a study investigating whether clock-gene polymorphisms predis-
pose to alcohol use identified an intronic variant in BMAL1 to be associated
with alcohol consumption in socially drinking controls but not in individuals
with alcohol dependence or abuse. 28

3. CLOCK

The first polymorphism identified in clock genes to be associated with
human phenotypes is a SNP located in the 3 0 -untranslated region (UTR) of
CLOCK , rs1801260 A/G. Subjects carrying the G allele have significantly
lower scores on the Horne- ¨ steberg (H ¨ ) questionnaire, which assays
morningness/eveningness preference and a lower score means eveningness
is preferred. 29 The G allele carriers show 10- to 44-min delay in preferred
timing for active and sleep phases. This finding of rs1801260 G allele asso-
ciating with evening preference was further validated by independent inves-
tigations. 30-32 However, there are also several studies that were not able to
observe this association between the G allele and eveningness, which may be
due to differences in ethnic heritages and/or linkages to other polymor-
phisms (reviewed in Refs. 33 and 34 ) .
Apart from playing a central role in the circadian clock, CLOCK is
believed to participate in the regulation of sleep as well. Based on H ¨ ques-
tionnaire, rs1801260 G/G homozygotes show significantly shorter sleep
duration and increased daytime sleepiness compared to individuals carrying
the A allele. 30,32,35 The association of rs1801260 and sleep has also been
observed in patients with psychiatric disorders. Among patients with major
depressive disorder (MDD) or bipolar disorder (BP), G/G homozygotes
exhibit significantly increased occurrence of sleep disturbance and BP
patients that are homozygous of the G allele show decreased need for sleep. 36
rs1801260 G/G homozygotes also demonstrate higher presence of insomnia
during antidepressant treatment. 37 Moreover,

in patients with major