CRY2 Is Associated with Rapid Cycling in Bipolar Disorder Patients

Bipolar disorder patients often display abnormalities in circadian rhythm, and they are sensitive to irregular diurnal rhythms. CRY2 participates in the core clock that generates circadian rhythms. CRY2 mRNA expression in blood mononuclear cells was recently shown to display a marked diurnal variation and to respond to total sleep deprivation in healthy human volunteers. It was also shown that bipolar patients in a depressive state had lower CRY2 mRNA levels, nonresponsive to total sleep deprivation, compared to healthy controls, and that CRY2 gene variation was associated with winter depression in both Swedish and Finnish cohorts.Four CRY2 SNPs spanning from intron 2 to downstream 3'UTR were analyzed for association to bipolar disorder type 1 (n = 497), bipolar disorder type 2 (n = 60) and bipolar disorder with the feature rapid cycling (n = 155) versus blood donors (n = 1044) in Sweden. Also, the rapid cycling cases were compared with bipolar disorder cases without rapid cycling (n = 422). The haplotype GGAC was underrepresented among rapid cycling cases versus controls and versus bipolar disorder cases without rapid cycling (OR = 0.7, P = 0.006-0.02), whereas overrepresentation among rapid cycling cases was seen for AAAC (OR = 1.3-1.4, P = 0.03-0.04) and AGGA (OR = 1.5, P = 0.05). The risk and protective CRY2 haplotypes and their effect sizes were similar to those recently suggested to be associated with winter depression in Swedes.We propose that the circadian gene CRY2 is associated with rapid cycling in bipolar disorder. This is the first time a clock gene is implicated in rapid cycling, and one of few findings showing a molecular discrimination between rapid cycling and other forms of bipolar disorder

Allele frequency association results for rapid cycling.

<p>Alleles, minor allele first.</p><p>*Ancestral allele in CEU population data (CEPH (Utah residents with ancestry from northern and western Europe)) from <a href="http://www.hapmap.org" target="_blank">www.hapmap.org</a>.</p><p>MAF, Minor allele frequencies for the affecteds (A) and unaffecteds (U).</p><p>ABD, anonymous blood donors.</p><p>Non-RC-BP, bipolar disorder patients without rapid cycling.</p><p>Odds ratio (OR), the proportion of minor versus major allele among affecteds (A)/proportion of minor versus major allele among unaffecteds (U).</p>a<p>Logistic regression with gender as covariate was used.</p><p>Empirical <i>P</i>-value (EMP1), Point-wise <i>P-</i>value from 10,000 permutations.</p

Haplotype association analysis results for rapid cycling.

<p>ABD, anonymous blood donors.</p><p>Non-RC-BP, bipolar disorder patients without rapid cycling.</p><p>Odds ratio (OR), the ratio specific haplotype versus all other haplotypes among the cases, relative to the ratio specific haplotype versus all other haplotypes among the controls.</p>a<p>Logistic regression with gender as covariate was used.</p