Circadian rhythm genes and sleep disturbances in the elderly

老年人的昼夜节律基因与睡眠障碍

• 批准号: 7903230
• 负责人: Gregory J. Tranah
• 金额: $ 31.73万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903230
• 关键词: Address; Affect; African American; Age Factors; Aging; Animal Model; Biology; Biometry; California; Candidate Disease Gene; Caring; Caucasians; Caucasoid Race; Characteristics; Circadian Rhythms; Cognition; Cognitive; Collection; Comorbidity; Complex; Consultations; DNA; Data; Data Set; Disease; Elderly; Evaluation; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Haplotypes; Health; Home environment; Human; Impaired cognition; Intervention; Lead; Longevity; Measures; Medical; Medical center; Melatonin; Mental Depression; Metabolism; Methods; Molecular Biology; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Observational Study; Outcome; Participant; Pathway interactions; Phenotype; Polysomnography; Population; Positioning Attribute; Predisposing Factor; Process; Productivity; Public Health; Quality of life; Regulation; Relative (related person); Research; Research Institute; Rest; Risk; Role; Safety; Sampling; San Francisco; Scientist; Signal Pathway; Single Nucleotide Polymorphism; Sleep; Sleep Disorders; Sleep disturbances; Stratification; Testing; Universities; Visit; Woman; Wrist; actigraphy; age group; age related; circadian pacemaker; cognitive function; cohort; cost; gene discovery; gene environment interaction; genetic epidemiology; genetic variant; improved; men; mortality; novel; older men; older women; osteoporosis with pathological fracture; prospective; public health relevance

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.

描述（由申请人提供）：老年人的睡眠障碍是普遍的，但往往未被诊断和治疗。“睡眠不佳”与各种年龄相关的疾病有关，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因素，并且关于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种昼夜节律和4种褪黑激素代谢基因中的常见遗传变异和单倍型，以确定其与通过活动记录仪测量的休息活动节律和睡眠特征的关联，以及与参与SOF和MrOS队列的两个前瞻性美国老年女性和男性队列中的认知功能、抑郁和死亡率的关联。在2002-2003年期间，在所有返回的高加索人和非洲裔美国人SOF参与者中记录了腕关节活动记录仪（n>2600，收集了DNA）。在2004-2005年的MrOS睡眠访问期间，2，846名白人和非洲裔美国人参与者（均具有可用的DNA）完成了腕关节活动记录和在家过夜多导睡眠记录。我们还包括所有具有可用DNA的非裔美国人，以提高我们检测基因型与死亡率，认知功能和抑郁症相关性的能力。这是世界上最大的客观睡眠数据和相关的心理，抑郁和健康数据集之一。我们独特的定位，以研究昼夜节律和褪黑激素代谢基因变异的作用在一个大样本。与招募、表型分析和DNA收集的成本相比，基因分型的成本将是很小的，这些成本已经在>5700名参与者中完成。2003年美国国家睡眠障碍研究中心提出的国家睡眠障碍研究计划要求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。了解睡眠障碍和认知障碍的根本原因和后果是公共卫生方面的一个高度优先事项。发现影响睡眠和其他年龄相关结果的基因多态性可能会导致对改善老年人口的健康，安全和生产力产生非常显著影响的干预措施。公共卫生关系：该项目将测试21种昼夜节律和4种褪黑激素代谢基因中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，认知功能和抑郁症相关。这是世界上最大的两个客观睡眠数据以及相关的心理、抑郁和健康数据的数据集，相对于已经完成的招募和表型分析的成本，基因型分析的成本很小。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。

项目成果

Genetic variants associated with sleep disorders.

• DOI: 10.1016/j.sleep.2014.11.003
• 发表时间: 2015-02
• 期刊: Sleep medicine
• 影响因子: 4.8
• 作者: Kripke DF;Kline LE;Nievergelt CM;Murray SS;Shadan FF;Dawson A;Poceta JS;Cronin J;Jamil SM;Tranah GJ;Loving RT;Grizas AP;Hahn EK
• 通讯作者: Hahn EK