Impact of genetic variants on sleep timing and type 2 diabetes risk

申请人（申请人）：25。800万美国人（8。3%）患有2型糖尿病，易患中风和心力衰竭。睡眠时间是2型糖尿病发展的一个未充分研究的风险因素，晚睡觉与糖尿病风险增加有关。最近的证据表明，“早晨型”个体的HbA 1c水平低于“晚上型”。睡眠时间特征（就寝时间，醒来时间和睡眠中点）是可遗传的（12-42%），但对潜在的遗传变异知之甚少。该提案旨在确定影响睡眠时间的新遗传因素，并与2型糖尿病的发展相互作用和影响。第一步是对多个种族的健康和糖尿病受试者的睡眠时间特征进行有效的全基因组关联研究。我们将员工创新混合物分析技术，在非裔美国人的主题，以及欧洲生物学的主题进行全基因组关联研究。这将标志着迄今为止最大的睡眠特征全基因组关联研究，并将确定与睡眠时间相关的遗传变异。研究结果将指出健康和糖尿病受试者中参与睡眠时间的新基因和途径。以前，睡眠和昼夜节律基因的遗传变异被发现与血糖特征有关，但尚不清楚睡眠时间的变化是否介导了这种关系。为了测试这一点，将在与2型糖尿病，睡眠时间和2型糖尿病状态相关的遗传变异之间进行中介分析。这将测试遗传变异影响糖尿病风险的机制是否是通过睡眠时间来实现的，从而为治疗睡眠时间作为糖尿病治疗的新途径打开了大门。最后，在某些情况下，睡眠时间可能会成为糖尿病遗传风险的敏感环境。为了测试这一点，将测试先前与2型糖尿病相关的变异与睡眠时间变量的相互作用。使用这种策略，遗传变异将B确定影响糖尿病的风险，只有在特定的睡眠时间条件下。这项研究的结果将确定影响睡眠时间的新遗传因素，并与2型糖尿病的发展相互作用和影响。这项工作将引起人们对睡眠时间调节在管理慢性病风险方面的公共卫生重要性的关注。通过这些结果，我们还将阐明睡眠和昼夜节律调节的潜在途径，以了解它们与心脏代谢疾病的机械联系，从而开辟潜在的新治疗途径。

DESCRIPTION (provided by applicant): 25. 8 million Americans (8. 3%) suffer from type 2 diabetes, which predisposes to stroke and heart failure. Timing of sleep is an understudied risk factor for development of type 2 diabetes, with later bedtime associated with increased risk of diabetes. Recent evidence suggests that "morning type" individuals have lower HbA1c levels compared to "evening types". Sleep timing traits (bedtime, wake time, and sleep midpoint) are heritable (12-42%), but the underlying genetic variation is poorly understood. This proposal aims to identify new genetic factors that affect sleep timing, and interact with and influence the development of type 2 diabetes. The first step is conducting well-powered genome-wide association studies of sleep timing traits in healthy and diabetic subjects across multiple ethnic groups. We will employee innovate admixture analysis techniques to perform a genome-wide association study in African American subjects, as well as subjects of European Ancestry. This will mark the largest genome-wide association study of sleep traits to date and will identify genetic variants which relate to sleep timing. The results will point to new genes and pathways involved in sleep timing in healthy and diabetic subjects. Previously, genetic variants in sleep and circadian genes were found to associate with glycemic traits, but it is unknown if changes to sleep timing mediate the relationship. To test this, mediation analysis will be performed between genetic variants associated with type 2 diabetes, sleep timing, and type 2 diabetes status. This will test if the mechanism by which genetic variants influence diabetes risk is through sleep timing, opening the door for treatment of sleep timing as a novel avenue of diabetes treatment. Lastly, sleep timing may act as a sensitizing environment for genetic risk on diabetes development in some cases. To test this, variants previously associates with type 2 diabetes will be tested for interaction with sleep timing variables. Using this strategy genetic variation will b identified which impacts diabetes risk under specific sleep timing conditions only. The results of this study will identify new genetic factors that affect sleep timing, and interact with and influence the development of type 2 diabetes. This work will bring attention to the public health importance of sleep timing regulation in managing risk of chronic disease. Through these results we will also elucidate pathways underlying sleep and circadian regulation to understand their mechanistic link to cardio-metabolic disease opening potential new avenues of treatment.