Is the molecular clock ticking differently in bipolar disorder? Methylation analysis of the clock gene ARNTL
Is the molecular clock ticking differently in bipolar disorder? Methylation analysis of the clock gene ARNTL
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DOI：
10.1080/15622975.2016.1231421
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发表时间：
2018-10-31
影响因子：
3.1
通讯作者：
Waha, Andreas
中科院分区：
文献类型：
--
作者：
Bengesser, Susanne A.;Reininghaus, Eva Z.;Waha, Andreas
目的：根据文献，时钟基因ARNTL与单胺氧化酶A的转录激活有关。因此，我们假设ARNTL的甲基化可能在双相情感障碍（BD）和对照组之间有所不同。方法：分析BD患者（n = 151）和对照组（n = 66）中覆盖ARNTL第一外显子（PS2）的一个CpG岛和ARNTL 5 '区（cg05733463）的一个位点的甲基化状态。使用EpiTect Bisulfite Kit、PCR和焦磷酸测序对空腹血液中的DNA进行亚硫酸转化，进行甲基化分析。协方差分析考虑协变量年龄、体重指数、性别、吸烟、锂和抗惊厥药物的摄入，以测试BD和对照组之间的甲基化差异。结果：BD患者ARNTL cg05733463位点甲基化显著高于对照组（F(1,209) = 44.500, P < 0.001）。相比之下，BD中PS2_POS1位点的甲基化显著低于对照组（F(1,128) = 5.787, P = 0.018）， PS2_POS2位点（F(1,128) = 3.033, P = 0.084）和POS7位点（F(1,34) = 3.425, P = 0.073）的甲基化趋势也明显低于对照组。结论：在BD和对照组中，ARNTL的甲基化有显著差异。因此，我们的研究表明，改变ARNTL的表观遗传调控可能为更好地理解双相障碍的昼夜节律和情绪波动提供机制基础。
Objectives: The clock gene ARNTL is associated with the transcription activation of monoamine oxidase A according to previous literature. Thus, we hypothesised that methylation of ARNTL may differ between bipolar disorder (BD) and controls. Methods: The methylation status of one CpG island covering the first exon of ARNTL (PS2) and one site in the 5 ' region of ARNTL (cg05733463) were analysed in patients with BD (n = 151) versus controls (n = 66). Methylation analysis was performed by bisulphite-conversion of DNA from fasting blood with the EpiTect Bisulfite Kit, PCR and pyrosequencing. Analysis of covariances considering the covariates age, body mass index, sex, smoking, lithium and anticonvulsant intake were performed to test methylation differences between BD and controls. Results: Methylation at cg05733463 of ARNTL was significantly higher in BD than in controls (F(1,209) = 44.500, P < .001). In contrast, methylation was significantly lower in BD at PS2_POS1 compared to controls (F(1,128) = 5.787, P = .018) and by trend at PS2_POS2 (F(1,128) = 3.033, P = .084) and POS7 (F(1,34) = 3.425, P = .073). Conclusions: Methylation of ARNTL differed significantly between BD and controls. Thus, our study suggests that altered epigenetic regulation of ARNTL might provide a mechanistic basis for better understanding circadian rhythms and mood swings in BD.