Molecular Circadian Disturbance in Human Blood Independently Predicts Multi-Disease Risk and Maps to Hepatic metabolism Pathways

Abstract Molecular circadian alterations take multiple forms, but quantifying them at scale is challenging in classic repetitive measurement-based studies. Here, we linked 312 hematological, biochemical, and metabolomic molecules to blood collection time in 420,746 UK Biobank participants, demonstrating widespread and profound circadian alterations. Using Bayesian Additive Regression Trees, we derived two orthogonal metrics of circadian alteration: phase shift, a global offset of molecular time relative to external time, and circadian disturbance, a quantitative readout of incoherence among individual molecular clocks. Whereas shift was primarily coupled to sleep behavior, disturbance was largely decoupled from it. Circadian disturbance independently predicted future risk for 98 incident conditions, including type 1 and type 2 diabetes, kidney and liver disease, with hazard ratios up to 1.51, and was significantly elevated in patients with 94 diseases. Genome-wide association analyses identified 51 loci for shift and 31 for disturbance (SNP-heritability 0.023 and 0.010, respectively), both converging on liver-specific pathways and lipid metabolism genes including APOE, PLTP, CETP, LDLR, and ANGPTL3. Our findings establish molecular circadian disturbance as an independent biomarker of multi-disease risk and implicate hepatic metabolic dysregulation in circadian incoherence.