Bipolar disorder (BD) is characterized by disruptions in circadian rhythms such as sleep and daily activity that often normalize after lithium treatment in responsive patients. As lithium is known to interact with the circadian clock, we hypothesized that variation in circadian 'clock genes' would be associated with lithium response in BD. We determined genotype for 16 variants in seven circadian clock genes and conducted a candidate gene association study of these in 282 Caucasian patients with BD who were previously treated with lithium. We found that a variant in the promoter of NR1D1 encoding Rev-Erbα (rs2071427) and a second variant in CRY1 (rs8192440) were nominally associated with good treatment response. Previous studies have shown that lithium regulates Rev-Erbα protein stability by inhibiting glycogen synthase kinase 3β (GSK3β). We found that GSK3β genotype was also suggestive of a lithium response association, but not statistically significant. However, when GSK3β and NR1D1 genotypes were considered together, they predicted lithium response robustly and additively in proportion to the number of response-associated alleles. Using lymphoblastoid cell lines from patients with BD, we found that both the NR1D1 and GSK3β variants are associated with functional differences in gene expression. Our findings support a role for Rev-Erbα in the therapeutic mechanism of lithium and suggest that the interaction between Rev-Erbα and GSK3β may warrant further study.
Pubmed ID: 21781277 RIS Download
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Portal to interactively visualize genomic data. Provides reference sequences and working draft assemblies for collection of genomes and access to ENCODE and Neanderthal projects. Includes collection of vertebrate and model organism assemblies and annotations, along with suite of tools for viewing, analyzing and downloading data.
View all literature mentionsSoftware program that computes sample size or power for association studies of genes, environmental factors, gene-environment interaction, or gene-gene interaction. Available study designs for a disease (binary) outcome include the unmatched case-control, matched case-control, case-sibling, case-parent, and case-only designs. Study designs for a quantitative tra it include independent individuals and case parent designs. Quanto is a 32-bit Windows application requiring Windows 95, 98, NT, 2000, ME or XP to run. The graphical user interface allows th e user to easily change the model and view the results without having to edit an input file and rerun the program for every model. The results of a session are stored to a log file. This log can be printed or saved to a file for reviewing at a later date. An option is included to create a text file of the log that can be imported into other documents. (entry from Genetic Analysis Software)
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