The architecture of exposome-phenome associations

Non-genetic exposures-including nutrients, lifestyle factors, consumables, and pollutants-substantially contribute to phenotypic variation. Most studies assess only a few exposures or phenotypes, yielding fragmented exposome-phenome relationships. Systematic approaches are needed to quantify how the exposome-the totality of environmental exposures-relates broadly to clinically relevant phenotypes. We developed a resource benchmarking the exposome's role using data from the National Health and Nutrition Examination Survey (NHANES), cataloging 619 exposures and 278 phenotypes, and systematically testing associations (Phenotype-exposure-wide association study [P-ExWAS]). Among ~119k associations, 5% (n=5,661) were Bonferroni significant, and 40% replicated across independent population samples. Single exposures explained modest variance (median R²=0.5%; interquartile range [IQR]: 0.27-1.10%). Twenty simultaneous exposome factors increased median variance explained to 3.5% (IQR: 1.8-7.8%), comparable to 1M genetic variants. The exposome-phenome atlas is available at: http://apps.chiragjpgroup.org/pe_atlas/.