Genetic architecture and analysis practices of circulating metabolites in the NHLBI Trans-Omics for Precision Medicine program

Authors: WANG, NANNAN - University Of Texas Health Science Center; OCKERMAN, FRANKLIN - University Of North Carolina; ZHOU, LAURA - Indiana University School Of Medicine; GROVE, MEGAN - University Of Texas Health Science Center; ALKIS, TARYN - University Of Texas Health Science Center; BARNARD, JOHN - Cleveland Clinic; BOWLER, RUSSELL - National Jewish Health; CLISH, CLARY - Broad Institute Of Mit/harvard; CHUNG, SHINYE - University Of Texas Health Science Center; DRZYMALLA, EMILY - University Of North Carolina; EVANS, ANNE - Metabolon, Inc; FRANCESCHINI, NORA - University Of North Carolina; GERSZTEN, ROBERT - Broad Institute Of Mit/harvard; GILLMAN, MADELINE - University Of North Carolina; HUTTON, SCOTT - Metabolon, Inc; KELLY, RACHEL - Brigham & Women'S Hospital; KOOPERBERG, CHARLES - Fred Hutchinson Cancer Research Center; LARSON, MARTIN - Boston University; LASKY-SU, JESSICA - Brigham & Women'S Hospital; MEYERS, DEBORAH - University Of Arizona; WOODRUFF, PRESCOTT - University Of California San Francisco (UCSF); REINER, ALEXANDER - University Of Washington; RICH, STEPHEN - University Of Virginia School Of Medicine; ROTTER, JEROME - Harbor-Ucla Medical Center; SILVERMAN, EDWIN - Brigham & Women'S Hospital; VASAN, RAMACHANDRAN - University Of Texas At San Antonio; WEISS, SCOTT - Brigham & Women'S Hospital; WONG, KARI - Metabolon, Inc; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); WU, LANG - University Of Hawaii; YARDEN, RONIT - National Heart, Lung And Blood Institute(NHLBI); BLACKWELL, THOMAS - University Of Michigan; SMITH, ALBERT - University Of Michigan; CHEN, HAN - University Of Texas Health Science Center; RAFFIELD, LAURA - University Of North Carolina; YU, BING - University Of Texas Health Science Center

Submitted to: The American Journal of Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/27/2025
Publication Date: 9/18/2025
Citation: Wang, N., Ockerman, F.P., Zhou, L.Y., Grove, M.L., Alkis, T., Barnard, J., Bowler, R.P., Clish, C.B., Chung, S., Drzymalla, E., Evans, A.M., Franceschini, N., Gerszten, R.E., Gillman, M.G., Hutton, S.R., Kelly, R.S., Kooperberg, C., Larson, M.G., Lasky-Su, J., Meyers, D.A., Woodruff, P.G., Reiner, A.P., Rich, S.S., Rotter, J.I., Silverman, E.K., Vasan, R.S., Weiss, S.T., Wong, K.E., Wood, A.C., Wu, L., Yarden, R., Blackwell, T.W., Smith, A.V., Chen, H., Raffield, L.M., Yu, B. 2025. Genetic architecture and analysis practices of circulating metabolites in the NHLBI Trans-Omics for Precision Medicine program. The American Journal of Human Genetics. 112(11):2720-2738. https://doi.org/10.1016/j.ajhg.2025.08.022.
DOI: https://doi.org/10.1016/j.ajhg.2025.08.022

Interpretive Summary: Metabolites are tiny molecules in our blood, which reflect both our nutritional status, and our risk of disease. Using data from more than 25,000 people of diverse backgrounds, this study identified hundreds of genetic regions that influence metabolite levels, including ones never reported before. These findings are important because metabolites are closely tied to nutrition and diet quality, and they may help explain how our diet and our genes work together to influence the likelihood we develop obesity, diabetes, and other chronic diseases. The study also showed that men and women can differ in how genes affect their metabolite levels, highlighting the need for sex-specific research in metabolism and nutrition. By providing best practices for analyzing metabolite data, this work sets a foundation for future studies across different populations. The results are may also eventually improve our ability to link genetics, diet, and chronic disease risk, ultimately informing more personalized prevention and treatment strategies.

Technical Abstract: Circulating metabolite levels partly reflect the state of human health and diseases and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single-study analyses. Leveraging the rich metabolomics resources generated by the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally diverse samples. From our comparison of multiple methods, we provided a set of reasonable strategies for outlier and imputation handling to process metabolite data and show that inverse normalization by study and half-minimum imputation provide mostly similar results for pooled or meta-analysis. Following the practical analysis framework, we further performed a genome-wide association analysis on 1,135 selected metabolites using whole-genome sequencing data from 16,359 individuals passing the quality-control filters and discovered 1,775 independent loci associated with 667 metabolites. Among 160 unreported locus-metabolite pairs, we identified associations with loci locating within previously implicated metabolite-associated genes, as well as associations with loci locating in genes such as GAB3 and VSIG4 (located on the X chromosome) that may play a role in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, which were located in well-known metabolic genes such as FADS2, D2HGDH, SUGP1, and UGT2B17, strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.