Diversity of Human Clock Genotypes and Consequences - Progress in Molecular Biology and Translational Science - page 70

delta power density change after sleep deprivation compared to wild type,
which indicates that the depth of the rebound of NREM sleep is affected in
h DEC2-P384R animals. Consistent with the mammalian data, expressing
m Dec2-P384R in the sleep/rest center of Drosophila brain leads to signifi-
cantly less sleep-like behavior with decreased sleep bout duration and
increased sleep bout number versus flies expressing m Dec2-WT . In sum-
mary, these results demonstrate DEC2 as an important player in the regu-
lation of sleep homeostasis.

17. TIMELESS
TIMELESS is associated with depression and sleep disturbances. 126
Four SNPs in or near the TIMELESS gene are linked to depression with
fatigue in females, while two of these SNPs (rs7486220 A/G and
rs1082214 C/T) are also linked to depression with early morning awakening
in males. Notably, rs7486220 A and rs1082214 C correlate with depression
with fatigue in females, whereas rs7486220 G and rs1082214 T correlate
with depression with early morning awakening in males. In a separate set
of individuals that do not have depression, rs1082214 C is correlated with
higher levels of seasonal changes in mood in females, while rs1082214
T is correlated with early morning awakening and fatigue in males. Collec-
tively, these data implicate a connection between TIMELESS and gender-
dependent depression and sleep regulation.

18. CONCLUDING REMARKS

Studies of human clock-gene variants reveal that besides circadian
timing, clock genes may also be involved in a number of other biological
processes ( Table 3.1 ) . Most of the clock-gene polymorphisms are associated
with sleep regulation, cancer development, metabolic traits, and mood dis-
orders, implying that these processes may have particularly close connections
with the circadian clock, and thus are more sensitive to alterations of the
clock caused by genetic variations. In addition, CLOCK , PER1-3 , and
CK1e

polymorphisms are linked to addiction, suggesting a role for the clock
in reward circuitry of the brain. BMAL1 and NPAS2 polymorphisms are
related to fertility and seasonal variations, supporting the long-held view that
circadian clock participates in seasonal adaptability. Furthermore, studies
using mice deficient for clock genes verified the involvement of clock genes