Circadian Clock Gene Polymorphisms Associated with Depression

描述（由申请人提供）：昼夜（每日）节律是人类健康的重要组成部分，尤其是精神健康。这些节律背后的“时钟”调节睡眠、警觉性、激素、各种组织的代谢活动以及许多其他生物过程。对这些过程进行适当的日常调节以获得最佳相位关系对心理健康至关重要。我们已经发现了两个生物钟基因的多态性与患有单相重度抑郁症（MDD）的人的睡眠和药物/酒精滥用表型的显着关联。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）的非典型定相，从而导致睡眠障碍和/或代谢障碍。该建议的中心假设是，抑郁症将过度睡眠和药物滥用的易感性推近“表型阈值”，并且我们在这两个时钟基因中鉴定的多态性调节这些基因的活性，以增强这些易感性，从而表达过度睡眠/药物滥用表型。我们将通过分析更大样本的抑郁症受试者的时钟基因多态性来验证这一假设，并将这些模式与非抑郁症受试者的特征对照人群的数据进行比较。此外，将使用哺乳动物细胞中时钟基因功能的最新发光测定法进行初步研究，以了解这些遗传多态性的功能细胞/分子基础。该项目适合NIH探索性/发展性研究资助计划，因为它建议开发一个新的研究领域，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：该项目将使用遗传技术研究人类日常生物钟和抑郁症之间的关系。特别是，嗜睡和药物/酒精滥用与抑郁症患者的生物钟基因相关。这项研究可能会导致新的基因诊断和/或治疗抑郁症患者的睡眠障碍和药物滥用的方法。

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.