Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
Genes Brain Behav. 2011 Nov;10(8):852-61. doi: 10.1111/j.1601-183X.2011.00725.x. Epub 2011 Sep 2.
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.
双相情感障碍（BD）的特征是昼夜节律紊乱，如睡眠和日常活动，在有反应的患者中，锂治疗后通常会恢复正常。由于锂已知与生物钟相互作用，我们假设昼夜“时钟基因”的变异与 BD 中的锂反应有关。我们确定了七个生物钟基因中的 16 个变体的基因型，并对 282 名以前接受过锂治疗的白种人 BD 患者进行了这些候选基因关联研究。我们发现，编码 Rev-Erbα 的 NR1D1 启动子中的一个变体（rs2071427）和 CRY1 中的第二个变体（rs8192440）与良好的治疗反应呈名义相关。先前的研究表明，锂通过抑制糖原合酶激酶 3β（GSK3β）来调节 Rev-Erbα 蛋白稳定性。我们发现 GSK3β 基因型也提示与锂反应有关，但无统计学意义。然而，当同时考虑 GSK3β 和 NR1D1 基因型时，它们可以稳健地预测锂反应，并按与反应相关的等位基因数量相加。使用 BD 患者的淋巴母细胞系，我们发现 NR1D1 和 GSK3β 变体均与基因表达的功能差异相关。我们的研究结果支持 Rev-Erbα 在锂治疗机制中的作用，并表明 Rev-Erbα 和 GSK3β 之间的相互作用可能值得进一步研究。
