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.
Morningness and eveningness are common traits, but little is known about how these changes reflecting internal circadian rhythm are caused at the molecular level, and how genetic variation in chronotype relates to metabolic disease. We will use human genetics and functional assays to understand the role of known and newly identified genes that contribute to differences in chronotype among individuals, and genetic relationship to metabolic phenotypes and outcomes. This work should inform knowledge of causes of morningness and eveningness, their link to metabolism and is relevant for leading to better prevention, diagnosis and therapies for circadian disorders and metabolic disease.
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