Circadian rhythm genes and sleep disturbances in the elderly

描述（由申请人提供）：老年人睡眠障碍普遍存在，但往往未得到诊断和治疗。“睡眠不佳”与多种与年龄有关的疾病有关，包括认知功能下降、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性因素，人们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。该项目将测试昼夜节律通路基因的遗传变异影响人类睡眠功能和其他与年龄相关的结果的假设。我们的具体目标是测试21个昼夜节律基因和4个褪黑素代谢基因的常见遗传变异和单倍型，这些基因与活动记录仪测量的休息活动节律和睡眠特征以及参与SOF和mrs队列的美国老年女性和男性的认知功能、抑郁和死亡率有关。在2002-2003年期间，对所有回国的高加索和非裔美国人SOF参与者进行了手腕活动记录（收集了DNA的约2600人）。在2004-2005年的mri睡眠访问期间，2,846名白种人和非裔美国人参与者（都有可用的DNA）完成了手腕活动仪和在家过夜的多导睡眠仪。我们还包括所有拥有可用DNA的非裔美国人，以提高我们检测基因型与死亡率、认知功能和抑郁症之间关联的能力。这是世界上最大的客观睡眠数据集以及相关的精神、抑郁和健康数据集之一。我们有独特的定位来研究大样本中昼夜节律和褪黑激素代谢基因变异的作用。与已经在5700名参与者中完成的招募、表型和DNA收集的成本相比，基因分型的成本将会很小。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呼吁对正常人类睡眠表型进行评估，并对“相关基因型”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潜在原因和后果是重中之重。发现影响睡眠和其他与年龄相关的结果的基因多态性，可能会导致对改善老年人的健康、安全和生产力产生重大影响的干预措施。公共卫生相关性：该项目将测试21个昼夜节律和4个褪黑激素代谢基因的遗传变异是否与参与骨质疏松性骨折和男性骨质疏松性骨折研究的老年男性和女性的休息活动节律和睡眠特征（通过活动记录仪测量）、死亡率、认知功能和抑郁相关。这是世界上最大的两个客观睡眠数据集以及相关的精神、抑郁和健康数据集，相对于已经完成的招募和表型的成本，基因分型的成本很小。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，对改善老年人的健康、生活质量和寿命产生非常重大的影响。

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.