Colgate University, Hamilton, New York.
J Biol Rhythms. 2018 Jun;33(3):318-336. doi: 10.1177/0748730418764540. Epub 2018 Apr 3.
Anxiety and other mood disorders, such as major depressive disorder (MDD) and seasonal affective disorder (SAD), affect nearly one-fifth of the global population and disproportionately affect young adults. Individuals affected by mood disorders are frequently plagued by sleep and circadian problems, and recent genetic studies provide ample support for the association of circadian and sleep syndromes with depression and anxiety. Mathematical modeling has been crucial in understanding some of the essential features of the mammalian circadian clock and is now a vital tool for dissecting how circadian genes regulate the molecular mechanisms that influence mood. Here, we model the effect of five clock gene polymorphisms, previously linked to mood disorders, on circadian gene expression and, ultimately, on the period length and amplitude of the clock, two parameters that dictate the phase, or alignment, of the clock relative to the environment. We then test whether these gene variants are associated with circadian phenotypes (Horne-Ostberg Morningness-Eveningness scores) and well-established measures of depression (Beck Depression Inventory) and anxiety (State-Trait Anxiety Inventory) in a population of undergraduates ( n = 546). In this population, we find significant allelic and/or genotypic associations between CRY2 and two PER3 variants and diurnal preference. The PER3 length polymorphism (rs57875989) was significantly associated with depression in this sample, and individuals homozygous for the PER3 single nucleotide polymorphism (SNP) (rs228697) reported significantly higher anxiety. Our simple model satisfies available experimental knockdown conditions as well as existing data on clock polymorphisms associated with mood. In addition, our model enables us to predict circadian phenotypes (e.g., altered period length, amplitude) associated with mood disorders in order to identify critical effects of clock gene mutations on CRY/BMAL binding and to predict that the intronic SNPs studied represent gain-of-function mutations, causing increased transcription rate. Given the user-friendly structure of our model, we anticipate that it will be useful for further study of the relationships among clock polymorphisms, circadian misalignment, and mood disorders.
焦虑症和其他情绪障碍，如重度抑郁症（MDD）和季节性情感障碍（SAD），影响了全球近五分之一的人口，并且不成比例地影响了年轻人。受情绪障碍影响的个体经常受到睡眠和昼夜节律问题的困扰，最近的遗传研究为昼夜节律和睡眠综合征与抑郁和焦虑的关联提供了充分的支持。数学建模对于理解哺乳动物昼夜节律钟的一些基本特征至关重要，现在是剖析昼夜节律基因如何调节影响情绪的分子机制的重要工具。在这里，我们模拟了先前与情绪障碍相关的五个时钟基因多态性对昼夜节律基因表达的影响，最终影响了时钟的周期长度和幅度，这两个参数决定了时钟相对于环境的相位或对准。然后，我们测试了这些基因变体是否与昼夜节律表型（Horne-Ostberg 早晨-傍晚倾向评分）和已建立的抑郁（贝克抑郁量表）和焦虑（状态-特质焦虑量表）测量值在大学生群体（n=546）中相关。在这个群体中，我们发现 CRY2 和两个 PER3 变体与昼夜偏好之间存在显著的等位基因和/或基因型关联。PER3 长度多态性（rs57875989）与该样本中的抑郁显著相关，并且 PER3 单核苷酸多态性（rs228697）纯合子个体报告的焦虑明显更高。我们的简单模型满足可用的实验敲低条件以及与情绪相关的时钟多态性的现有数据。此外，我们的模型使我们能够预测与情绪障碍相关的昼夜节律表型（例如，周期长度、幅度改变），以识别时钟基因突变对 CRY/BMAL 结合的关键影响，并预测研究的内含子 SNPs 代表功能获得性突变，导致转录率增加。考虑到我们模型的用户友好结构，我们预计它将有助于进一步研究时钟多态性、昼夜节律失调和情绪障碍之间的关系。
