CRY2 Is Associated with Rapid Cycling in Bipolar Disorder Patients

Abstract

BackgroundBipolar 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.Principal FindingsFour 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.ConclusionsWe 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.

Clock genes in human alcohol abuse and comorbid conditions

“…In addition, currently, there are no published data from Cry2 mutant mice on tests that induce anxiety-like or depressive-like behaviors, or on their alcohol intake. As such, this finding supports the view that CRY2 is clearly a "mood gene", since it is associated with a range of depressive phenotypes, including winter depression, on the basis of major depressive disorder (Lavebratt, Sjöholm, Soronen, et al, 2010), bipolar disorder (Sjöholm, Backlund, et al, 2010), the depressive episode of bipolar disorder (Lavebratt, Sjöholm, Soronen, et al, 2010), a chronic course of depressive symptoms due to major depressive disorder or bipolar disorder (Fiedorowicz, Coryell, Akhter, & Ellingrod, 2012), and dysthymia that is chronic depression (Kovanen, Kaunisto, Donner, Saarikoski, & Partonen, 2013).…”

“…Mansour et al (2009) found no association with bipolar disorder in their further analysis of 252 SNPs of 18 genes in 523 patients with bipolar type 1 disorder and 477 controls, but NPAS2 rs17025005 and CRY2 rs1554338 suggested nominal associations with bipolar type 1 disorder. Further, the hypothesis-driven study by Sjöholm, Backlund, et al (2010) tested whether the 4 SNPs of CRY2 that had been associated with winter depression using samples of 204 patients and 2107 controls from two independent population-based studies (Lavebratt, Sjöholm, Soronen, et al, 2010) are associated with bipolar disorder. In a sample of 712 patients with bipolar disorder and 1044 controls, two risk haplotypes and one protective haplotype in CRY2 were identified for bipolar disorder with the feature of rapid cycling (Sjöholm, Backlund, et al, 2010).…”

“…Further, the hypothesis-driven study by Sjöholm, Backlund, et al (2010) tested whether the 4 SNPs of CRY2 that had been associated with winter depression using samples of 204 patients and 2107 controls from two independent population-based studies (Lavebratt, Sjöholm, Soronen, et al, 2010) are associated with bipolar disorder. In a sample of 712 patients with bipolar disorder and 1044 controls, two risk haplotypes and one protective haplotype in CRY2 were identified for bipolar disorder with the feature of rapid cycling (Sjöholm, Backlund, et al, 2010). The study by Lavebratt, Sjöholm, Soronen, et al (2010) demonstrated that CRY2 mRNA expression, as assessed from peripheral blood mononuclear cells at several times during one-night sleep deprivation, was decreased in depressed patients with bipolar disorder, as compared with controls, and that total sleep deprivation did not induce any increase in CRY2 mRNA levels in the non-responsive patients opposite to the change seen in the controls.…”

Chronobiology of Bipolar Disorder: Therapeutic Implication

“…Similarly, Nr1d1 profile was found to be advanced during mania, when the amplitude of the gene expression profile was found higher compared to depression [23]. Moreover, the transcription of Chryptochrome 2, which has recently been found associated with bipolar rapid cycling disorder [96], was shown to be reduced in bipolar depressed patients compared to healthy controls.…”

The bipolarity of light and dark: A review on Bipolar Disorder and circadian cycles

“…It has been associated with rapid cyclers (Sjoholm, Backlund et al 2010). More recently, a variant in CRY1 (rs8192440) was nominally associated with good treatment response to lithium (McCarthy, Nievergelt et al 2011).…”