biostudies-literatureUnknownPatel CJNIDDK NIH HHSNIEHS NIH HHSNon-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 samplemedRxiv : the preprint server for health sciences2025.06.05.25329055https://www.ebi.ac.uk/biostudies/studies/S-EPMC12259201biostudies-literatureThe architecture of exposome-phenome associations.PMC12259201U24 ES036819R01 ES032470R01 DK137993Patel CJIoannidis JPManrai AKfalseThe 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 sample2025-01-01T00:00:00Z2025 Jun2025-08-27T03:11:21.269Z2025-08-27T03:11:21.269ZS-EPMC122592014066126410.1101/2025.06.05.25329055