Genome-wide mapping of common and rare variant effects on adiposity across childhood

Abstract Our understanding of the genetic architecture of obesity is primarily based on studies of adults, with sparser data from childhood. Here, we conducted age-stratified genetic association studies against objectively measured ( n = 62,276) or recalled childhood adiposity-related traits ( n eff = 599,924), identifying 624 common variants associated with childhood adiposity, with one-third having no concordant association with adult body mass index. Signals linked to the leptin–melanocortin pathway ( BSX , GNAS , LEPR and PCSK1 ) and incretin signaling ( GIPR and GLP1R ) showed childhood-specific effects on adiposity. Single-nucleus RNA sequencing data identified childhood-specific adiposity-regulating cell populations in the arcuate nucleus and mammillary bodies, indicating neurocircuits that regulate adiposity specifically during childhood. Finally, sequencing in 479,615 individuals uncovered rare protein-coding variation in ADCY3 , CALCR , MC4R , MRAP2 , POMC and MYH13 , exhibiting stronger associations in childhood than in adults. Our findings suggest that childhood provides a more sensitive window for the study of key endocrine and neuropeptide pathways that regulate energy balance.

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Journal
Nature Genetics
Published
2026-09-25
DOI
https://doi.org/10.1038/s41588-026-02772-y
Primary Topic
Regulation of Appetite and Obesity
Type
article
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article

Genome-wide mapping of common and rare variant effects on adiposity across childhood

Nicolás Fragoso-Bargas, Pål R. Njølstad, Stephen O’Rahilly, Ken K. Ong et al.
Nature Genetics
Regulation of Appetite and Obesity
article

Genome-wide mapping of common and rare variant effects on adiposity across childhood

Nicolás Fragoso-Bargas, Pål R. Njølstad, Stephen O’Rahilly, Ken K. Ong, Ole A. Andreassen, Stefan E. Johansson, Brian Y.H. Lam, Robin J. Hofmeister, Lena R Kaisinger, John R. B. Perry, Alexandra Havdahl, Marc Vaudel, Georgina K.C. Dowsett, Katherine A. Kentistou, Adrián Cortés, Felix R. Day, Giles S.H. Yeo, Yajie Zhao, Sam M. Lockhart, Lukas Steuernagel, Zoltán Kutalik, Roya Karimi, John A. Tadross, Lieven Clement, Yancy Lo, Jimmy Z. Liu, Eirik Bratland, Jens C. Brüning, Jonas Sundfjord, Adina Elena Lupu, Jonathan Davitte
article en

Abstract

Abstract Our understanding of the genetic architecture of obesity is primarily based on studies of adults, with sparser data from childhood. Here, we conducted age-stratified genetic association studies against objectively measured ( n = 62,276) or recalled childhood adiposity-related traits ( n eff = 599,924), identifying 624 common variants associated with childhood adiposity, with one-third having no concordant association with adult body mass index. Signals linked to the leptin–melanocortin pathway ( BSX , GNAS , LEPR and PCSK1 ) and incretin signaling ( GIPR and GLP1R ) showed childhood-specific effects on adiposity. Single-nucleus RNA sequencing data identified childhood-specific adiposity-regulating cell populations in the arcuate nucleus and mammillary bodies, indicating neurocircuits that regulate adiposity specifically during childhood. Finally, sequencing in 479,615 individuals uncovered rare protein-coding variation in ADCY3 , CALCR , MC4R , MRAP2 , POMC and MYH13 , exhibiting stronger associations in childhood than in adults. Our findings suggest that childhood provides a more sensitive window for the study of key endocrine and neuropeptide pathways that regulate energy balance.

Nature Genetics
Queen's University Belfast (GB), Oslo University Hospital (NO), Norwegian Institute of Public Health (NO), University of Oslo (NO), Age UK (GB), Haukeland University Hospital (NO), Cambridge University Hospitals NHS Foundation Trust (GB), Ghent University (BE), Lovisenberg Diakonale Høgskole (NO), Max Planck Institute for Metabolism Research (DE), Precision for Medicine (United States) (US), Wellcome/MRC Institute of Metabolic Science (GB), Institut thématique Génétique, génomique et bioinformatique (FR), ID Genomics (United States) (US), Centre universitaire de médecine générale et santé publique, Lausanne (CH), University of Bergen (NO), University of Lausanne (CH)
Good health and well-being
Openalex Percentile: Top 15%
Regulation of Appetite and Obesity
DOIOpen Access PDFOpenAlex
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