Title: Time for change in prevalent cardiometabolic diseases: the role of the circadian system.
Abstract: Sleep disturbances and circadian rhythm disruption are increasingly recognised as integral components of cardiometabolic disease, including hyperglycaemia, type 2 diabetes (T2D), and obesity. Epidemiological and experimental studies support strong bidirectional relationships between sleep, glycaemic control, and metabolic health, yet the genetic architecture underlying these links remains incompletely understood. It remains unclear whether shared genetic signals reflect direct causal effects, correlated but independent biological processes, or broader coordination across physiological systems.
In the first part of this talk, we present a large-scale human genetics framework to evaluate shared genetic architecture between sleep-related traits, circulating glycaemic biomarkers, and T2D. Using genome-wide association data, we integrate genetic correlation, Mendelian randomisation, and Bayesian colocalisation to identify genomic regions harbouring shared genetic signals across these domains. Rather than treating sleep and metabolic traits as isolated outcomes, this work highlights loci where their genetic architectures intersect, prioritising shared signals that implicate pathways involved in circadian regulation, glucose homeostasis, and metabolic control.
In the second part of the talk, we introduce ongoing work developing multivariate phenotyping and modelling strategies for sleep and cardiometabolic traits. These approaches aim to capture coordinated genetic influences across related physiological systems, including genetic variation structure across multiple phenotypic dimensions. By organising genetic signals across sleep and metabolic traits jointly, this work seeks to identify latent axes of variation and to generate hypotheses about how coordinated or dysregulated biological processes contribute to cardiometabolic risk.
Together, this work illustrates how combining locus-level analyses with multivariate genetic frameworks can extend our understanding of the biological links between sleep, circadian regulation, and cardiometabolic disease. By focusing on shared structure across traits rather than isolated associations, these approaches provide a foundation for exploring system-level organisation and for prioritising pathways and mechanisms for future investigation.
Biographies:
Prof David Ray
David Ray is Professor of Endocrinology, Head of the Oxford Centre for Diabetes, Endocrinology and Metabolism, and Co Director of the Sir Jules Thorn Sleep and Circadian Neuroscience Institute, all at the University of Oxford. He is an internationally recognised physician–scientist whose work bridges glucocorticoid biology, and sleep and circadian medicine. His research is distinguished by the integration of fundamental molecular discovery with direct relevance to human disease.
Ray made seminal contributions to endocrine oncology through his work on ectopic ACTH syndrome, identifying loss of glucocorticoid sensitivity in non-pituitary tumours as the key mechanism permitting aberrant ACTH production. He defined the genetic and epigenetic bases for reduced glucocorticoid receptor expression and demonstrated that glucocorticoid sensitivity is dynamic and environmentally modulated, including by tobacco smoke carcinogens. These findings provided a unifying mechanistic framework for a complex clinical disorder.
His research on the hypothalamic–pituitary–adrenal axis extended to pituitary corticotroph biology, where he discovered a novel immune–endocrine interface mediated by gp130 cytokines and JAK–STAT signalling. This work defined pathways linking immune signals to ACTH gene regulation, cell proliferation, and differentiated endocrine function.
Ray subsequently made major advances in understanding glucocorticoid receptor signalling and variability in clinical responses to anti-inflammatory therapy. Using advanced live-cell imaging, he identified previously unrecognised roles for the glucocorticoid receptor during mitosis and linked disrupted glucocorticoid function to tumourigenesis.
In recent years, Ray has been at the forefront of translating circadian biology into human medicine. He has led international consortia using the UK Biobank to identify genetic determinants of sleep and chronotype and to apply Mendelian randomisation to establish causal links with neuropsychiatric and inflammatory disease. Complementary experimental studies defined the circadian clock in macrophages, identified clock-modulating small molecules, and revealed a time-of-day-dependent anti-inflammatory function of circadian machinery in both immune and non-immune cells. He also uncovered a REV-ERBα-mediated circuit linking circadian timing to glucocorticoid action and cellular metabolism.
Dr Daniel Rosoff
Daniel B. Rosoff is a postdoctoral research associate in the Radcliffe Department of Medicine at the University of Oxford and a researcher at the Novo Nordisk Research Centre Oxford. He completed his DPhil in 2025 through the NIH Oxford–Cambridge Scholars Program, training jointly at the University of Oxford and the U.S. National Institutes of Health (National Institute on Alcohol Abuse and Alcoholism). His doctoral work was supervised by Prof. David Ray, Prof. George Davey Smith, Prof. Constantinos Christodoulides, and Dr. Falk W. Lohoff.
Rosoff’s research focuses on the use of human genetics and genetic epidemiology to identify causal mechanisms underlying cardiometabolic and neuropsychiatric disease. His work integrates Mendelian randomization, multivariate GWAS, fine-mapping, and multi-omic data to dissect shared and disease-specific biological pathways contributing to psychiatric–cardiometabolic multimorbidity, with a particular focus on sleep and circadian regulation. A defining feature of his research is an emphasis on causal inference and generalisability across populations through the integration of large-scale genomic and functional datasets.
In his current postdoctoral role, supervised by Prof. David Ray at Oxford in collaboration with Dr. Wei Gan at Novo Nordisk, Rosoff applies multivariate genetic discovery and functional interpretation to understand the biological links between sleep, circadian rhythms, physical activity, and metabolic disease. His work aims to bridge population-scale genetic discovery with translational insight, supporting the prioritization of biologically grounded targets and pathways relevant to human disease and therapeutic development.
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