Circadian Clock Gene Polymorphisms Associated with Depression

描述（由申请人提供）：昼夜节律是人类健康，尤其是心理健康的重要组成部分。这些节律背后的“时钟”调节着睡眠、警觉性、激素、各种组织的代谢活动和许多其他生物过程。适当的日常调节这些过程以达到最佳的阶段关系对心理健康至关重要。我们发现，患有单极重度抑郁症（MDD）的人类中，两种生物钟基因多态性与睡眠和药物/酒精滥用表型存在显著关联。时钟基因多态性可导致人类昼夜节律系统（或其他代谢途径）的非典型相位，从而导致睡眠障碍和/或代谢障碍。该提议的中心假设是，抑郁症将嗜睡和药物滥用的易感性推向了“表型阈值”，我们在这两个时钟基因中发现的多态性调节了这些基因的活动，从而增强了这些易感性，从而表达了嗜睡/药物滥用的表型。我们将通过在更大的抑郁症受试者样本中分析生物钟基因多态性来检验这一假设，并将这些模式与来自非抑郁症受试者特征控制人群的数据进行比较。此外，了解这些遗传多态性的功能细胞/分子基础的初步研究将使用最先进的哺乳动物细胞时钟基因功能发光测定法进行。这个项目适合美国国立卫生研究院探索性/发展性研究资助计划，因为它提出了一个新的研究领域，即生物钟、抑郁症和遗传学之间的接口，这将有助于预测、诊断和治疗与抑郁症相关的表型。公共卫生相关性：该项目将使用基因技术研究人类日常生物钟与抑郁症之间的关系。特别是，嗜睡和药物/酒精滥用与抑郁症患者的生物钟基因有关。这项研究可能会导致新的基因方法来诊断和/或治疗抑郁症患者的睡眠障碍和药物滥用。

DESCRIPTION (provided by applicant): Circadian (daily) rhythms are a crucial component of human health, especially of mental health. The "clocks" underlying these rhythms regulate sleep, alertness, hormones, metabolic activities of various tissues, and many other biological processes. Appropriate daily regulation of these processes to attain optimal phase relationships is crucial for mental health. We have discovered significant associations of polymorphisms in two circadian clock genes with sleep and drug/alcohol abuse phenotypes in humans suffering from unipolar Major Depressive Disorder (MDD). Clock gene polymorphisms can cause atypical phasing of the human circadian system (or of other metabolic pathways) leading to sleep disorders and/or metabolic disorders. The central hypothesis of this proposal is that depression pushes the susceptibilities for hypersomnia and substance abuse closer to a "phenotype threshold," and that the polymorphisms we have identified in these two clock genes modulate the activities of these genes so as to enhance those susceptibilities such that the hypersomnia/substance abuse phenotypes are expressed. We will test that hypothesis by analyzing clock gene polymorphisms in a larger sample of depressed subjects and compare those patterns with data from a characterized control population of non-depressed subjects. In addition, initial studies towards understanding the functional cell/molecular basis for these genetic polymorphisms will be conducted using state-of-the art luminescence assays of clock gene function in mammalian cells. This project is appropriate for the NIH Exploratory/Developmental Research Grant Program because it proposes to develop an novel research area-namely the interface between circadian clocks, depression, and genetics-that will facilitate the prediction, diagnosis, and treatment of phenotypes related to depression. PUBLIC HEALTH RELEVANCE: This project will use genetic techniques to study the relationship between daily biological clocks and depression in humans. In particular, hypersomnia and drug/alcohol abuse are correlated with biological clock genes in depressed humans. This investigation could lead to new genetic methods of diagnosis and/or treatment of sleep disorders and substance abuse in depressed humans.