Sleep duration Polygenic Risk Score: Association with cognition and brain measures

项目摘要/摘要 睡眠是整体健康和幸福的重要指标，具有许多功能，包括必不可少的作用 潜在的认知加工。睡眠的改变在认知健康的人和那些 神经退行性疾病，如阿尔茨海默病、痴呆症(AD)[1-4]。因此，睡眠障碍一直是 被描述为认知衰退和阿尔茨海默病事件的重要风险因素[5-8]。更具体地说，睡眠时间短 持续时间与认知能力低下和大脑皮层β-淀粉样蛋白(Aβ)负荷增加有关，这是一种先兆 认知衰退/痴呆症[9-11]。此外，基因组的可变性也被报道为一种显著的 认知功能和神经变性疾病的贡献者[12-16]。多基因风险分数(PR)已被 在过去几年中不断改进，以提供更好的疾病风险预测评估[17]。 据报道，用于评估AD风险的PRSS是认知和不同睡眠的重要预测因子 在老年人和青年中采取措施[18]。我们最近展示了关于两者之间关系的初步数据 基于睡眠的认知障碍与认知[19]。据报道，也有证据表明睡眠与 和大脑结构[20-22]，然而，大多数研究检查个人的大脑测量。尽管工作繁重 探索睡眠和认知之间的联系，研究睡眠、睡眠遗传学和 整个年龄段认知健康的成年人的认知仍然很稀少。目前的提案旨在 研究睡眠PR之间的联系，总结睡眠持续时间的遗传贡献[23-26]， 与认知有关，而大脑的作用衡量了这种联系。分析样品将包括~1900个 认知健康的成年人(20-80岁)来自两个队列；参考能力神经网络/认知 保护区(RANN/CR)和华盛顿高地-因伍德哥伦比亚老龄项目(WHICAP)。具体目标 是为了：a)从横向和横向两个方面描述睡眠PR和认知之间的关联 纵向上，b)确定大脑测量如何调节这些关联，以及c)通过以下方式扩展工作 创建认知PR，以类似的方式对其进行评估，并检查与睡眠PR的重叠。 此K99/R00应用程序提供了一项计划，将支持申请者在成为 独立研究人员专注于描述遗传学和认知之间的联系，而 研究大脑测量在这种联系中的作用。此应用程序中的活动在资源中设置- 丰富的环境将为申请者提供新的技能，深化和加强她在以下方面的专业知识：1) 遗传学，2)神经成像，3)认知行为数据的横截面和纵向分析，以及4) 负责任的研究行为。哥伦比亚大学的环境、培训计划和 指导团队不仅将为应聘者提供一系列新的方法和技能， 她作为一名独立的研究科学家，但也将产生一系列知识，将澄清如何睡眠 遗传学与认知健康的参与者在成年年龄范围内的认知能力有关。

PROJECT SUMMARY/ABSTRACT Sleep is a vital indicator of overall health and well-being, and serves many functions including essential roles underlying cognitive processing. Changes in sleep are common among cognitively healthy individuals and those with neurodegenerations such as Alzheimer’s disease dementia (AD)[1-4]. Thus, sleep disturbances have been characterized as significant risk factors for cognitive decline and incident AD[5-8]. More specifically, short sleep duration has been linked to poor cognitive performance and greater cortical β-amyloid (Aβ) burden, a precursor to cognitive decline/ dementia[9-11]. Furthermore, genomic variability has been also reported as a significant contributor to cognitive function and neurodegenerative disorders[12-16]. Polygenic Risk Scores (PRS) have been improving over the last years to provide a better assessment of disease risk predictions[17]. PRSs developed to assess risk of AD were reported as significant predictors of cognition and different sleep measures in elderly and in youth [18]. We recently showed preliminary data regarding the association between sleep-based PRS (Sleep PRS) and cognition[19]. There is also reported evidence of an association between sleep and brain structure[20-22], however, the majority of studies examine individual brain measures. Despite work exploring the association between sleep and cognition, research on the link among sleep, sleep genetics and cognition in cognitively healthy adults across the age range remains sparse. The current proposal aims to investigate the association between a Sleep PRS, summarizing the genetic contribution to sleep duration[23-26], with cognition, and the role of brain measures to this association. The analytical sample will consist of ~1900 cognitively healthy adults (20-80 y.o.) drawn from two cohorts; the Reference Abilities Neural Networks/Cognitive Reserve (RANN/CR), and the Washington Heights-Inwood Columbia Aging Project (WHICAP). The specific aims are to: a) characterize the association between Sleep PRS and cognition both cross-sectionally and longitudinally, b) identify how brain measures might mediate these associations, and c) expand the work by creating a Cognitive PRS, evaluating it in a similar manner, and examining overlap with the Sleep PRS. This K99/R00 application presents a program that will support the applicant on a path towards becoming an independent investigator focused on characterizing the association between genetics and cognition, while examining the role of brain measures in this association. The activities in this application are set in a resource- rich environment that will provide the applicant with new skills, deepening, and strengthen her expertise in: 1) genetics, 2) neuroimaging, 3) cross-sectional and longitudinal analyses of cognitive behavior data, and 4) the responsible conduct of research. The combination of the environment at Columbia University, training plan, and mentorship team will not only provide the candidate with a spectrum of new methods and skills that will establish her as an independent research scientist, but will also produce a body of knowledge that will clarify how sleep genetics are associated with cognition in cognitively healthy participants across the adult age-range.