Multi-omics architecture of childhood obesity and metabolic dysfunction uncovers biological pathways and prenatal determinants

Stratakis, Nikos; Anguita Ruiz, Augusto; Fabbri, Lorenzo; Maitre, Léa; González, Juan Ramón; Basagaña Flores, Xavier; Borràs, Eva; Nieuwenhuijsen, Mark J.; Sabidó Aguadé, Eduard, 1981-; Urquiza, José M.; Bustamante Pineda, Mariona; Vrijheid, Martine

doi:http://dx.doi.org/10.1038/s41467-025-56013-7

Multi-omics architecture of childhood obesity and metabolic dysfunction uncovers biological pathways and prenatal determinants

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Stratakis 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/s41467-025-56013-7

Abstract

Childhood 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.