Disrupted Diurnal Phase Variation in Circulating Factors as a Predictor of Disease and Mortality

Abstract Maintaining normal diurnal rhythms is critical for human health, yet due to limited longitudinal sampling, the oscillatory patterns of most circulating molecular factors and their alteration in pathology remain poorly characterized. Here, we used large-scale cross-sectional UK Biobank plasma data to identify daytime (diurnal phase) oscillations in more than 3,200 biomarkers. Most plasma components exhibited significant oscillatory patterns, including 98% of lipoproteins, 90% of complete blood count measures, and 56% of proteins. We further validated the enrichment of proteomic oscillations in an independent 48-hour serial sampling cohort. Approximately 25% of oscillatory biomarkers displayed sex-specific patterns, particularly hormones, phosphate regulators, immune mediators, and muscle proteins. Remodeling of oscillatory patterns was associated with pathological states, with many alterations detectable years before clinical diagnosis. We derived a composite time-of-day deviation risk score (TOD-RS) strongly associated with all-cause mortality (HR=1.40 per SD, p < 1 × 10 −16 ). These findings highlight the pervasive nature of daytime oscillatory regulation, its disruption in disease, and the potential use of oscillatory biomarkers for risk stratification and early disease detection.