Stratakis, NikosAnguita Ruiz, AugustoFabbri, LorenzoMaitre, LéaGonzález, Juan RamónBasagaña Flores, XavierBorràs, EvaNieuwenhuijsen, Mark J.Sabidó Aguadé, Eduard, 1981-Urquiza, José M.Bustamante Pineda, MarionaVrijheid, Martine2025-02-252025-02-252025Stratakis N, Anguita-Ruiz A, Fabbri L, Maitre L, González JR, Andrusaityte S, et al. Multi-omics architecture of childhood obesity and metabolic dysfunction uncovers biological pathways and prenatal determinants. Nat Commun. 2025 Jan 14;16(1):654. DOI: 10.1038/s41467-025-56013-72041-1723http://hdl.handle.net/10230/69728Childhood obesity poses a significant public health challenge, yet the molecular intricacies underlying its pathobiology remain elusive. Leveraging extensive multi-omics profiling (methylome, miRNome, transcriptome, proteins and metabolites) and a rich phenotypic characterization across two parts of Europe within the population-based Human Early Life Exposome project, we unravel the molecular landscape of childhood obesity and associated metabolic dysfunction. Our integrative analysis uncovers three clusters of children defined by specific multi-omics profiles, one of which characterized not only by higher adiposity but also by a high degree of metabolic complications. This high-risk cluster exhibits a complex interplay across many biological pathways, predominantly underscored by inflammation-related cascades. Further, by incorporating comprehensive information from the environmental risk-scape of the critical pregnancy period, we identify pre-pregnancy body mass index and environmental pollutants like perfluorooctanoate and mercury as important determinants of the high-risk cluster. Overall, our work helps to identify potential risk factors for prevention and intervention strategies early in the life course aimed at mitigating obesity and its long-term health consequences.application/pdfeng© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-025-56013-7BiomarkersObesityRisk factorsinfo:eu-repo/semantics/openAccess