Genetics of chronotype and impact on metabolic disease

身体内部昼夜节律时间保持机制的失调是一种 代谢性疾病的危险因素。时间类型，或睡眠时间偏好 在24小时的一天中，是潜在的昼夜节律的行为表现 这可以通过大规模的问卷调查来评估。时间类型是遗传的 从大规模的GWAS，强大的潜在遗传变异涉及昼夜节律， 已经发现了其他途径，为理解生物学提供了机会。 昼夜节律紊乱对人体生理的原因和后果。我们 假设鉴定出遗传关联下因果变异， 表征罪犯突变的分子、细胞和生理功能 和基因之间的因果遗传关系的解剖 和代谢疾病的研究将有助于 阐明生理时钟在健康、肥胖和2型糖尿病风险中的作用。为了 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 已知的全基因组显著和新发现的时间型的基础变异 使用大的公开可用的基因型和自我报告的时间型（n~ 500 k）的基因座， 客观睡眠时间信息（n~ 100 k）; 2）确定分子、细胞和 在人类模型中使用的分析的因果变异体和基因的生理效应， 现有资源、实验分析和独特的受控实验室内样品 系统评价时间型基因的多基因重叠 和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定时的机械联系， 2型糖尿病，为昼夜节律的治疗开辟了潜在的新途径 2型糖尿病的治疗

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.