CRY2 is associated with rapid cycling in bipolar disorder patients

• Published in: PloS one Vol. 5; no. 9; p. e12632
• Main Authors: Sjöholm, Louise K, Backlund, Lena, Cheteh, Emarndeena Haji, Ek, Inger Römer, Frisén, Louise, Schalling, Martin, Osby, Urban, Lavebratt, Catharina, Nikamo, Pernilla
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.09.2010; Public Library of Science (PLoS)
• Subjects: 3' Untranslated regions; Abnormalities; Alcoholism; Analysis; Bipolar disorder; Bipolar Disorder - genetics; Bipolar Disorder - psychology; Blood; Blood donation; Blood donors; Case-Control Studies; Circadian rhythm; Circadian rhythms; Clock gene; Cry2 gene; Cryptochromes; Cryptochromes - genetics; Cycles; Diurnal; Gene expression; Genes; Genetic aspects; Genetics and Genomics/Complex Traits; Genetics and Genomics/Medical Genetics; Genomes; Genomics; Genotype; Haplotypes; Humans; Leukocytes (mononuclear); Medicin och hälsovetenskap; Medicine; Mental depression; Mental Health/Mood Disorders; Mitochondrial DNA; Neurosciences; Patients; Population; RNA; Single-nucleotide polymorphism; Sleep; Sleep deprivation; Studies; Surgery; Sweden; Winter; Sweden
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0012632

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.