Phenomic environment-wide association study (PheEWAS) models complexity in the exposome

Abstract Phenome-wide association studies (PheWAS) have successfully identified genomic-based interrelationships between phenotypes but seldom consider environmental exposures. Here, in a phenomic environment-wide association study (PheEWAS), we interrogated relationships between 326 exposures and 55 phenotypes for ∼19,000 participants of the National Health and Nutrition Examination Survey (NHANES). Linear regression models adjusted for age, sex, socioeconomic status, BMI, race/ethnicity, and survey year identified and replicated 106 significant exposure–phenotype associations after Bonferroni correction. The top association was for alpha-tocopherol (vitamin E) with triglycerides (Discovery p = 1.16 × 10⁻¹¹; Replication p = 8.05 × 10⁻¹³). The exposure retinol (vitamin A) had the largest number of individual replicating associations (14 phenotypes including total calcium, iron-binding capacity, ferritin, albumin, transferrin saturation, creatinine, gamma-glutamyl transferase, triglycerides, uric acid, alkaline phosphatase, hemoglobin, and blood urea nitrogen). The phenotype with the greatest number of exposure associations was homocysteine (associated with thiamine; alpha- and gamma-tocopherol; dietary fiber, protein, and potassium; riboflavin; cotinine; folate; phosphorus; cadmium; iron intake; supplement count; and niacin). A race/ethnicity-stratified analysis revealed 11 unique population-specific associations. Our findings demonstrate PheEWAS a method to provide new details on the complexity of the exposome at the level of the phenome Competing Interest Statement The authors have declared no competing interest. Funding Statement This work is supported by the USDA National Institute of Food and Agriculture and Hatch Appropriations under Project #PEN04275 and Accession #1018544 Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The National Health and Nutrition Examination Survey (NHANES) is a population survey implemented by the Centers for Disease Control and Prevention (CDC) to monitor the health of the United States whose data is publicly available in hundreds of files. This Data Descriptor describes a single unified and universally accessible data file, merging across 255 separate files and stitching data across 4 surveys, encompassing 41,474 individuals and 1,191 variables. The variables consist of phenotype and environmental exposure information on each individual, specifically (1) demographic information, physical exam results (e.g., height, body mass index), laboratory results (e.g., cholesterol, glucose, and environmental exposures), and (4) questionnaire items. Second, the data descriptor describes a dictionary to enable analysts find variables by category and human-readable description. The datasets are available on DataDryad and a hands-on analytics tutorial is available on GitHub. Through a new big data platform, BD2K Patient Centered Information Commons (http://pic-sure.org), we provide a new way to browse the dataset via a web browser (https://nhanes.hms.harvard.edu) and provide application programming interface for programmatic access. https://datadryad.org/dataset/doi:10.5061/dryad.d5h62 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes This version of the manuscript has been revised to update figure legibility on page 34. Data Availability Data Availability More information on the data is available on Dryad (https://doi.org/10.5061/dryad.d5h62) All code, QC files, and result files can be found on GitHub (https://github.com/HallLab/PheEWAS_paper/tree/main)