The architecture of exposome-phenome associations

Non-genetic exposures comprising the "exposome," including diet, lifestyle, infections, and pollutants, shape many clinical phenotypes, yet the evidence remains fragmented. We conducted an Exposome-Wide Association study (ExWAS) incorporating 619 exposure indicators and 305 quantitative phenotypes across 10 independent waves of the US Centers for Disease Control and Prevention National Health and Nutrition Examination Survey (CDC NHANES). Replicable and stable signals were most concentrated in cardiometabolic and anthropometric phenotypes, linking objective nutrient biomarkers and lipophilic pollutants with body mass index, glycated hemoglobin, and lipid profiles. Triglycerides, an important marker for cardiovascular risk, emerged as the phenotype most strongly associated with multi-domain exposures, notably trans fatty acids, persistent pollutants, and vitamin E isoforms. In pulmonary traits, tobacco-specific and carcinogen biomarkers were more prominently associated with reduced lung function than short-lived nicotine metabolites, refining exposomic links to Forced Expiratory Volume in 1 second (FEV1). While individual exposures showed modest effects, aggregate "poly-exposomic" models explained phenotypic variation comparable to genome-wide polygenic scores. Exposome globes further reveal an interconnected architecture where exposures rarely act in isolation, complicating causal attribution while providing a more holistic view of environmental risk. Our findings highlight which exposures are most likely to add value to disease risk assessment, population surveillance, as well as further exposure prioritization and next-generation longitudinal exposomics.