Circadian rhythm genes and sleep disturbances in the elderly

描述(申请人提供)：老年人的睡眠障碍很普遍，但经常没有得到诊断和治疗。“睡眠不佳”与各种与年龄相关的疾病有关，包括认知功能减退、抑郁和死亡率。睡眠-觉醒调节是一个复杂的过程，涉及环境影响和遗传易感因素，对昼夜节律基因变异对人类睡眠功能和年龄相关结果的影响知之甚少。这个项目将检验这样一种假设，即昼夜节律途径基因的遗传变异会影响人类的睡眠功能和其他与年龄相关的结果。我们的具体目标是测试21个昼夜节律和4个褪黑素代谢基因的常见遗传变异和单倍型，以确定它们与静息活动节律和睡眠特征以及参与SOF和MROS队列的两个预期美国老年男女队列中的认知功能、抑郁和死亡率之间的关系。在2002-2003年间，对所有回归的高加索人和非裔美国人的SOF参与者(收集了DNA，n&gt；2600人)进行了腕部活动描记。在2004-2005年的MRO睡眠访问期间，2846名高加索人和非裔美国人参与者(都有可用的DNA)完成了手腕动作图和在家过夜多导睡眠图。我们还包括所有拥有可用DNA的非裔美国人，以提高我们检测与死亡率、认知功能和抑郁症相关的基因的能力。这是世界上可用的最大的客观睡眠数据和相关的精神、抑郁和健康数据集之一。我们在研究昼夜节律和褪黑素代谢基因变异在大样本中的作用方面具有得天独厚的优势。与已经在5700名参与者身上完成的招募、表型分析和DNA采集的成本相比，基因分型成本将很低。由国家睡眠障碍研究中心提出的2003年国家睡眠障碍研究计划要求对人类正常睡眠表型进行评估，并对“相关基因类型”进行全面评估，以确定异常睡眠或昼夜节律改变的遗传基础。就公共卫生而言，了解睡眠障碍和认知障碍的根本原因和后果是一个高度优先的问题。发现影响睡眠和其他与年龄相关的结果的基因多态性可能会导致干预措施，对改善老年人口的健康、安全和生产力具有非常重要的影响。公共卫生相关性：该项目将测试21个昼夜节律和4个褪黑素代谢基因的遗传变异是否与参与男性队列中骨质疏松性骨折和骨质疏松性骨折研究的老年男性和女性的休息活动节奏和睡眠特征(通过活动记录仪测量)、死亡率、认知功能和抑郁有关。这是世界上可用的客观睡眠数据和相关精神、抑郁和健康数据的两个最大数据集，相对于已经完成的招募和表型分析的成本，基因分型成本很小。发现影响睡眠和年龄相关结果的基因可能会导致干预措施，对改善老年人口的健康、生活质量和寿命具有非常重要的影响。

DESCRIPTION (provided by applicant): Sleep disorders among the elderly are pervasive, yet frequently undiagnosed and untreated. 'Poor sleep' has been associated with a variety of age-related conditions, including reduced cognitive function, depression and mortality. Sleep-wake regulation is a complex process involving environmental influences and genetic predisposing factors and little is known about the effect of circadian gene variants on human sleep function and age-related outcomes. This project will test the hypothesis that genetic variations in circadian pathway genes affect human sleep function and other age-related outcomes. Our specific aims are to test common genetic variants and haplotypes in 21 circadian rhythm and 4 melatonin metabolism genes for association with rest activity rhythms and sleep characteristics as measured by actigraphy, and with cognitive function, depression and mortality in two prospective cohorts of elderly U.S. women and men participating in the SOF and MrOS cohorts. During 2002-2003, wrist actigraphy was recorded in all returning Caucasian and African American SOF participants (n>2600 with DNA collected). During the MrOS sleep visit in 2004-2005, 2,846 Caucasian and African American participants (all with available DNA) completed wrist actigraphy and in-home overnight polysomnography. We are also including all African Americans with available DNA to improve our power to detect genotype associations with mortality, cognitive function and depression. This is one of the largest data sets of objective sleep data and associated mental, depression, and health data available in the world. We are uniquely positioned to examine the role of circadian rhythm and melatonin metabolism gene variants in a large sample. Compared to the cost of recruitment, phenotyping, and DNA collection, which have already been accomplished in >5700 participants, the genotyping cost will be small. The 2003 National Sleep Disorders Research Plan as put forward by The National Center on Sleep Disorders Research calls for an assessment of normal human sleep phenotypes and a full evaluation of "associated genotypes" to define the genetic underpinning of abnormal sleep or altered circadian rhythm profiles. Understanding the underlying causes and consequences of sleep disturbances and cognitive impairments is a high priority in terms of public health. Discovering gene polymorphisms that affect sleep and other age-related outcomes could lead to interventions that have a very significant impact on improving health, safety, and productivity of the elderly population. PUBLIC HEALTH RELEVANCE: This project will test whether genetic variants in the 21 circadian rhythm and 4 melatonin metabolism genes are associated with rest activity rhythms and sleep characteristics (as measured by actigraphy), mortality, cognitive function and depression in older men and women participating in the Study of Osteoporotic Fractures and Osteoporotic Fractures in Men cohorts. These are two of the largest data sets of objective sleep data and associated mental, depression, and health data available in the world and relative to the costs of recruitment and phenotyping, which have already been accomplished, the genotyping cost is small. Discovering genes that affect sleep and age-related outcomes could lead to interventions that have a very significant impact on improving health, quality of life and longevity on the elderly population.