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

Nikos Stratakis (), Augusto Anguita-Ruiz, Lorenzo Fabbri, Léa Maitre, Juan R. González, Sandra Andrusaityte, Xavier Basagaña, Eva Borràs, Hector C. Keun, Lida Chatzi, David V. Conti, Jesse Goodrich, Regina Grazuleviciene, Line Småstuen Haug, Barbara Heude, Wen Lun Yuan, Rosemary McEachan, Mark Nieuwenhuijsen, Eduard Sabidó, Rémy Slama, Cathrine Thomsen, Jose Urquiza, Theano Roumeliotaki, Marina Vafeiadi, John Wright, Mariona Bustamante and Martine Vrijheid
Additional contact information
Nikos Stratakis: Institute for Global Health (ISGlobal)
Augusto Anguita-Ruiz: Institute for Global Health (ISGlobal)
Lorenzo Fabbri: Institute for Global Health (ISGlobal)
Léa Maitre: Institute for Global Health (ISGlobal)
Juan R. González: Institute for Global Health (ISGlobal)
Sandra Andrusaityte: Vytautas Magnus University
Xavier Basagaña: Institute for Global Health (ISGlobal)
Eva Borràs: Universitat Pompeu Fabra (UPF)
Hector C. Keun: Imperial College London
Lida Chatzi: University of Southern California
David V. Conti: University of Southern California
Jesse Goodrich: University of Southern California
Regina Grazuleviciene: Universitat de Barcelona (UB)
Line Småstuen Haug: Norwegian Institute of Public Health
Barbara Heude: Center for Research in Epidemiology and StatisticS (CRESS)
Wen Lun Yuan: Center for Research in Epidemiology and StatisticS (CRESS)
Rosemary McEachan: Bradford Teaching Hospitals NHS Foundation Trust
Mark Nieuwenhuijsen: Institute for Global Health (ISGlobal)
Eduard Sabidó: Universitat Pompeu Fabra (UPF)
Rémy Slama: Université Grenoble Alpes
Cathrine Thomsen: Norwegian Institute of Public Health
Jose Urquiza: Institute for Global Health (ISGlobal)
Theano Roumeliotaki: University of Crete
Marina Vafeiadi: University of Crete
John Wright: Bradford Teaching Hospitals NHS Foundation Trust
Mariona Bustamante: Institute for Global Health (ISGlobal)
Martine Vrijheid: Institute for Global Health (ISGlobal)

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56013-7

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