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Genetics of chronotype and impact on metabolic disease

时间型遗传学及其对代谢疾病的影响

基本信息

批准号：
9176615
负责人：
RICHA SAXENA
金额：
$ 42.75万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9176615
关键词：
Acute Behavioral Beta Cell Bioinformatics Biological Biological Assay Biological Models Cell Line Cells Chronic Disease Circadian Dysregulation Circadian Rhythms Computer Analysis Data Set Defect Development Diabetes Mellitus Diagnosis Disease Dissection Epidemiologic Studies Etiology Gene Mutation Genes Genetic Genetic Risk Genetic Variation Genotype Glucose Goals Health Hepatocyte Hour Human Human Genetics Individual Insulin Intervention Knowledge Laboratories Laboratory Study Link Maps Metabolic Metabolic Diseases Metabolism Modeling Molecular Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Pathway interactions Patient Self-Report Phase Phenotype Physiological Physiology Plant Roots Play Population Predisposition Prevention Proteins Questionnaires Randomized Regulation Resources Risk Risk Factors Role Signal Transduction Sleep Testing Time Variant Work base biobank blood glucose regulation circadian pacemaker diabetic evidence base genetic association genetic variant genome wide association study genome-wide glucose production glucose tolerance insulin secretion loss of function metabolic phenotype mouse model obesity risk precision medicine preference prevent prospective sample collection shift work sleep onset trait uptake

项目摘要

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.

人体内部昼夜节律计时机制的失调是一种疾病