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

项目总结/摘要 睡眠是整体健康和福祉的重要指标，具有许多功能，包括重要作用 潜在的认知过程睡眠的变化在认知健康的个体中很常见， 神经退行性疾病，如阿尔茨海默病痴呆（AD）[1-4]。因此，睡眠障碍一直是 特征为认知能力下降和AD事件的显著风险因素[5-8]。更确切地说，睡眠不足 持续时间与认知能力差和皮质β淀粉样蛋白（Aβ）负荷增加有关，A β是一种前体蛋白， 认知能力下降/痴呆[9-11]。此外，基因组变异性也被报道为一个重要的遗传学因素。 认知功能和神经退行性疾病的贡献者[12-16]。多基因风险评分（PRS） 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PRS是认知和不同睡眠的重要预测因子。 老年人和青年人[18]。我们最近展示了关于 睡眠PRS（Sleep PRS）和认知[19]。也有证据表明睡眠与 和大脑结构[20-22]，然而，大多数研究都是对个体大脑的测量。尽管工作 探索睡眠和认知之间的联系，研究睡眠，睡眠遗传学和 在整个年龄范围内，认知健康的成年人的认知能力仍然很少。目前的建议旨在 研究睡眠PRS之间的关联，总结睡眠持续时间的遗传贡献[23-26]， 与认知的关系，以及大脑对这种联系的作用。分析样品将包含约1900 认知健康的成年人（20-80岁）从两个队列中抽取;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化项目（WHICAP）。具体目标 a）表征睡眠PRS和认知之间的关联， 纵向，B）确定大脑测量如何介导这些关联，以及c）通过以下方式扩展工作 创建认知PRS，以类似的方式对其进行评估，并检查与睡眠PRS的重叠。 这个K99/R 00申请提出了一个计划，将支持申请人的道路上成为 独立研究人员专注于描述遗传学和认知之间的关联， 研究大脑测量在这种关联中的作用。此应用程序中的活动设置在资源中- 丰富的环境，将为申请人提供新的技能，深化，并加强她的专业知识：1） 遗传学，2）神经影像学，3）认知行为数据的横截面和纵向分析，以及4） 负责任地进行研究。结合哥伦比亚大学的环境，培养计划， 导师团队不仅将为候选人提供一系列新的方法和技能， 她作为一个独立的研究科学家，但也将产生一个知识体系，将澄清如何睡眠 遗传学与整个成年年龄范围内认知健康参与者的认知有关。

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.