Genetics of chronotype and impact on metabolic disease

Massachusetts General Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

Project Summary/ Abstract Dys-regulation of the body's internal circadian time-keeping mechanism is an established risk factor for metabolic disease. Chronotype, or preference in timing of behaviors during the 24 hour day, reflects underlying circadian rhythms and can be assessed by questionnaires and actigraphy in large populations. Our long-term goal is to use human genetics to elucidate pathways that link sleep and circadian regulation to cardio-metabolic disease with the aim to develop therapeutic interventions that leverage insights from human genetic approaches. The overall objective of this application is to identify the variants, genes, and mechanisms responsible for chronotype and understand how alterations in biological timing of these genes interfaces with metabolic physiology and disease. In the first funding period, we identified 351 novel loci for chronotype, sleep and activity timing traits by leading and contributing to GWAS of circadian and sleep traits in the UK Biobank. We identified genetic variants implicating circadian rhythms and also insulin regulation pathways, providing opportunities to understand the biological causes and consequences of circadian rhythm disturbances and their relationship with human metabolic physiology. We hypothesize that more complete identification of causal common, rare and structural variants by whole genome sequencing, clustering of variants by multi-trait associations and tissue- and cell-type specific annotations, as well as functional genomic analyses of pleiotropic signals between chronotype and metabolic disease using computational and experimental approaches will illuminate circadian rhythm pathways and the mechanisms linking them to type 2 diabetes. In the next phase of this research, we leverage whole- genome sequencing, proteomics and metabolomics in large biobanks including UK Biobank and TOPMed cohorts as well as high-throughput experimental perturbation studies to pursue the following specific aims: 1) to characterize common, rare and structural genetic variants underlying chronotype using genome sequencing; 2) to dissect mechanistic pathways by which variants and genes influence chronotype using analyses of existing multi-omic resources as well as experimental assays, and 3) to define molecular links between chronotype, daily molecular and behavioral rhythms and T2D by analyses of pleiotropy, colocalization and gene x behavior associations. This work will reveal mechanistic links 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.