Elucidation of Genetic Effects on Sleep and Circadian Traits

项目摘要 睡眠和昼夜节律在维持身心健康方面起着至关重要的作用， 这些领域的干扰与重大公共卫生后果有关。尽管大量的 流行病学证据将睡眠和昼夜节律特征与不同的病理联系起来，但对睡眠和昼夜节律特征知之甚少。 这些特征背后的遗传因素。睡眠和昼夜节律特征，如失眠和时钟类型， 高度遗传性和家庭聚集性，表明相当大比例的风险是由于遗传。 在利用全基因组关联研究确定这些性状的风险变异方面已经取得了进展 （GWAS）。然而，GWAS的结果主要存在于基因组的非编码区，很少精确定位 实际效应基因的精确位置。越来越多的证据表明，简单地将GWAS 在最近的基因组区域中编码的基因的信号并不总是准确的。因此，GWAS本身是 主要有益于信号发现，而不是功能基因发现。在阐明实际的困难， 人GWAS信号的效应基因是鉴定新的GWAS信号分子调节因子的重要障碍。 睡吧尽管广泛的工具利用模型系统和体外方法来进行这种功能性研究， 分析，以及计算方法牵连因果变量，这些方法是利用不足， 睡眠和昼夜节律领域。这项建议旨在通过雇用一个团队来填补这一关键的知识空白 科学方法，汇集了睡眠和昼夜节律基因组学的专业知识， 人类、模型系统和计算生物学，同时利用现有的大型数据集 基因发现。在目标1中，我们将利用现有的生物银行数据来发现失眠的风险变体 和chronotype。随后，在目标2中，将通过一组空间基因组分析进行检查， 这些基因座使用IPSC衍生的神经祖细胞来鉴定致病变体。最后，我们将确定 基因具有功能相关性，使用果蝇作为模型系统。我们的总体假设是， 变异与失眠的行为表现和生理时钟类型密切相关， 尖端的分子方法将阐明致病变异和相应的效应基因， 这些地方。我们的目标是将遗传信息转化为对患者护理有意义的益处， GWAS的正确功能背景确定了参与这些性状的基因组变异，并了解了它们如何 他们在这种背景下运作。

PROJECT SUMMARY Sleep and circadian rhythms play critical roles in the maintenance of physical and mental health, with disturbances in these domains associated with major public health consequences. Despite the abundance of epidemiological evidence linking sleep and circadian traits to diverse pathologies, little is known about the genetic factors that underlie these traits. Sleep and circadian traits, such as insomnia and chronotype, are highly heritable and aggregate in families, suggesting a substantial proportion of risk is due to genetics. Progress has been made in identifying risk variants for these traits using genome-wide association studies (GWAS). However, GWAS results principally reside in non-coding regions of the genome and rarely pinpoint the precise location of the actual effector genes. Mounting evidence is indicating that simply attributing GWAS signals to the genes encoded in the closest genomic regions is not always accurate. As such, GWAS alone is primarily beneficial to signal discovery, not functional gene discovery. The difficulty in elucidating the actual effector genes for human GWAS signals is a significant barrier to identifying novel molecular regulators of sleep. Despite wide-ranging tools utilizing model systems and in vitro approaches to conduct such functional analyses, as well as computational methods to implicate causal variants, these approaches are underutilized in the sleep and circadian domain. This proposal seeks to fill this critical knowledge gap by employing a team science approach, bringing together expertise in the genomics of sleep and circadian rhythms that spans humans, model systems, and computational biology, while simultaneously leveraging large existing datasets for genetic discovery. In Aim 1, we will leverage existing biobank data for discovery of risk variants for insomnia and chronotype. This will be followed, in Aim 2, by examination via a battery of spatial genomic analyses of these loci using IPSC-derived neuro progenitor cells to identify causal variants. Finally, we will determine which genes have functional relevance using Drosophila as a model system. Our global hypothesis is that genomic variation is strongly associated with the behavioral manifestation of insomnia and chronotype and that our cutting-edge molecular approaches will elucidate the causal variants and the corresponding effector genes at these loci. We aim to translate genetic information into meaningful benefits for patient care by uncovering the correct functional context of GWAS identified genomic variants involved in these traits and understanding how they operate in this context.