Genetics of chronotype and impact on metabolic disease

DYS-调节人体内部的昼夜节律机制是一种 已确定的代谢性疾病的危险因素。时型，或睡眠时间偏好 在24小时内，是潜在的昼夜节律的行为表现 这可以通过在大量人口中进行问卷调查来评估。时型是可遗传的 从大规模的GWA中，强大的潜在遗传变异牵涉到昼夜节律和 已经发现了其他途径，为理解生物 昼夜节律紊乱对人体生理的原因和后果。我们 假设识别出遗传关联背后的因果变异， 罪犯突变的分子、细胞和生理功能的表征 和基因，以及对时型变异之间因果遗传关系的剖析 使用计算和实验方法的代谢性疾病将会有所帮助 阐明时型在健康、肥胖和2型糖尿病风险中的作用。按顺序 为了验证这些假设，我们提出了以下具体目标：1)确定因果关系 已知的全基因组显着和新发现的年型背后的变异 使用大的公开可获得的基因型和自我报告的年代型的基因座(n~500k)和 客观睡眠时间信息(n~100k)；2)确定分子、细胞和 人体模型中因果变异和基因的生理学效应分析 现有资源、实验分析和独特的实验室内受控样本 收集；3)系统评价时型基因的多基因重叠 以及2型糖尿病易感性的途径。这项工作将建立知识 有必要了解内部昼夜节律的计时机制与 2型糖尿病，开辟了治疗昼夜节律的潜在新途径 疾病和2型糖尿病。

Dys-regulation of the body's internal circadian time-keeping mechanism is an established risk factor for metabolic disease. Chronotype, or sleep-timing preference during the 24 hour day, is a behavioral manifestation of underlying circadian rhythms that can be assessed by questionnaires in large populations. Chronotype is heritable and from large-scale GWAS, robust underlying genetic variants implicating circadian and other pathways have been found, providing opportunities to understand the biological causes and consequences of circadian rhythm disturbances on human physiology. We hypothesize that identification of causal variants underlying genetic associations, characterization of the molecular, cellular and physiologic function of culprit mutations and genes, and dissection of causal genetic relationships between chronotype variants and metabolic disease using computational and experimental approaches will help illuminate the role of chronotype in health, obesity and risk of type 2 diabetes. In order to test these hypotheses, we propose the following specific aims: 1) To identify causal variants underlying known genome-wide significant and newly discovered chronotype loci using large publicly available genotype and self-reported chronotype (n~500k) and objective sleep timing information (n~100k); 2) To determine the molecular, cellular and physiologic effects of causal variants and genes in human models using analyses of existing resources, experimental assays and unique controlled in-laboratory sample collections; and 3) To systematically evaluate the polygenic overlap of chronotype genes and pathways with type 2 diabetes susceptibility. This work will build the knowledge necessary to understand the mechanistic link of timing of the internal circadian rhythm to type 2 diabetes, opening potential new avenues of treatment for circadian rhythm disorders and type 2 diabetes.