Diversity of Human Clock Genotypes and Consequences - Progress in Molecular Biology and Translational Science - page 65

Three SNPs in CRY2 are linked to winter depression, including one of
the SNPs that have been reported to be associated with the risk of breast
cancer and non-Hodgkin lymphoma. 112 Molecular analysis revealed that
the levels of CRY2 mRNA are decreased in depressed bipolar patients.
While a night of total sleep deprivation results in significant upregulation
of CRY2 transcript in control subjects, it fails to do so in depressed bipolar
patients. Both the genetic and molecular studies suggest that dysregulation of
CRY2 expression may be involved in vulnerability to depression.

10. REV-ERBa
REV-ERBa is primarily implicated in BP. A haplotype comprised of

two SNPs located in intron 1 and 5 0 -UTR of REV-ERBa , respectively, is

significantly associated with BP. 113 Furthermore, a SNP in the intronic
region of REV-ERBa

, rs2314339 C/T, is associated with long-term efficacy
of lithium carbonate therapy in BP. 114 The frequency of the T allele is sig-
nificantly increased in nonresponders, and patients carrying the T allele are
3.5 more likely to show no improvement or even worsening of the illness.

Consistently, another SNP located in the promoter region of REV-ERBa
correlates with good treatment response and changes in REV-ERB a
expression in response to lithium treatment. 115 These findings support a role
for REV-ERB a in the therapeutic mechanism of lithium.

11. CK1«
A SNP in the 3 0 -UTR of CK1e is significantly associated with self-

reported response to D -amphetamine. 116 Consistently, quantitative trait loci
(QTL) analysis in mice selectively bred for high versus low sensitivity to
methamphetamine identified a QTL in the Ck1e gene that may cause the

difference in response to methamphetamine. 117 Expression differences of
Ck1e is also observed in mouse lines displaying high versus low sensitivity

to methamphetamine. Collectively, human and animal studies suggest that
CK1 e contributes to variability in stimulant response.
An intronic SNP of CK1e is linked to BP and prostate cancer. 23,43 Fur-

thermore, another variant in CK1e correlates with testosterone to dihydro-

testosterone ratio in the serum, which may contribute to the pathology of
prostate cancer. 69