Our understanding of the genetic architecture of obesity has primarily been shaped by observations from adult populations with relatively few studies on childhood obesity. To address this gap, we conduct a longitudinal genetic association study in up to ∼600,000 individuals with objectively measured or recalled childhood adiposity-related traits. We identify 624 common variant signals (only 7% are previously reported) associated with childhood adiposity, of which one third have no concordant association with adult BMI. Signals linked to the leptin-melanocortin pathway (BSX, GNAS, LEPR and PCSK1) and incretin-signalling genes (GIPR and GLP1R) show stronger associations in childhood than in adults, suggesting that childhood provides a more sensitive window for detecting variation in key endocrine and neuropeptide pathways regulating energy balance. This observation is further supported by integrating single-nucleus RNA sequencing data from the human hypothalamus, identifying childhood-specific adiposity-regulating cell populations in the arcuate nucleus and mammillary bodies, indicating distinct neuro-circuits that regulate adiposity only during childhood. Three signals showed parent-of-origin specific associations with childhood BMI, at KLF14 (maternal-specific), GNAS (parental-discordant) and ZDBF2 (paternal-specific). Finally, we complement these common variant analyses with DNA sequence data in 479,615 individuals, identifying rare protein-coding variation in ADCY3, CALCR, MC4R, MRAP2, POMC and MYH13, all of which demonstrate stronger adiposity associations in childhood than in adults. Collectively, our findings emphasize the value of expanding research on childhood adiposity alongside studies focused on adult obesity measures.

J.R.B.P. and K.A.K. are employees/shareholders of Insmed Inc. J.R.B.P. also receives research funding from GSK and consultancy fees from WW International Inc. Y.Z. was a UK University worker at GSK during this work. J.L., A.C., Y.L. and J.D. are employees/shareholders of GSK. G.S.H.Y. receives grant funding from Novo Nordisk and Amgen, and consults for both Novo Nordisk and Eli Lilly and Company. J.C.B. is co-founder of Cerapeutix and has received research funding through collaborations with Sanofi Aventis and Novo Nordisk, he also consulted for Eli Lilly and Company and Novo Nordisk. B.Y.H.L consults for Nuntius Therapeutics. S.O has undertaken remunerated consultancy work for Pfizer, Third Rock Ventures, AstraZeneca, NorthSea Therapeutics and Courage Therapeutics. OAA is consultant to Cortechs.ai and Precision Health AS, and received speaker's honorarium from Lilly, BMS, Jannsen and Lundbeck. The remaining authors declare no competing interests.

This work was supported by grants (to S.J) from Helse Vest's Open Research Grant (#912250 and F-12144), the Novo Nordisk Foundation (NNF20OC0063872) and the Research Council of Norway (#315599). J.S. and S.J. was supported by the Meltzer Research Fund. K.A.K., L.R.K. Y.Z., F.R.D., J.R.B.P., and K.K.O. were supported by the UK Medical Research Council (MC_UU_00006/2) and the NIHR Cambridge Biomedical Research Centre. M.V. was supported by the Research Council of Norway (#301178), the European Research Council (#101171420), and the University of Bergen. J.A.T., B.Y.H.L. and G.S.H.Y. are supported by BBSRC Project Grant (BB/S017593/1) and the MRC Metabolic Diseases Unit (MC_UU_00039/1). G.K.C.D. is supported by a BBSRC iCASE studentship co-financed by Novo Nordisk. LS and JCB are supported by Novo Nordisk A/S, the German National Diabetes Centre (DZD) and European Research Council (ERC) grant (SYNEME: 742106). S.O is supported by the MRC Metabolic Diseases Unit (MC_UU_00039/1) and the NIHR Cambridge Biomedical Research Centre (NIHR203312). S.L. is supported by a Wellcome Trust Clinical PhD Fellowship (225479/Z/22). MoBa: This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Health Authorities and Stiftelsen Kristian Gerhard Jebsen, and in collaboration with deCODE Genetics. We further thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authorities. We thank the MoBaPsychGen team, led by Elizabeth Corfield, for providing quality controlled genotype data, supported by funding from the South-Eastern Norway Regional Health Authority (#2021045; #2020022; #2022083; 2018058). ALSPAC: The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf); this research was specifically funded by Wellcome Trust and MRC (core) (076467/Z/05/Z). ALSPAC GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

MoBa: Informed consent was obtained from all study participants. The administrative board of the Norwegian Mother, Father and Child Cohort Study led by the Norwegian Institute of Public Health approved the study protocol. The establishment of MoBa and initial data collection was based on a license from the Norwegian Data Protection Agency and approval from The Regional Committee for Medical Research Ethics. The MoBa cohort is currently regulated by the Norwegian Health Registry Act. The study was approved by The Regional Committee for Medical Research Ethics (#2012/67). UK Biobank: Informed consent was obtained from all study participants. The study has approval from the North West Multicentre Research Ethics Committee as a Research Tissue Bank. ALSPAC: Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data from the Norwegian Mother, Father and Child Cohort Study used in this study are managed by the Norwegian Institute of public health and can be made available to researchers, provided approval from the Regional Committees for Medical and Health Research Ethics (REC), compliance with the EU General Data Protection Regulation (GDPR) and approval from the data owners. The consent given by the participants does not open for storage of data on an individual level in repositories or journals. Researchers who want access to data sets for replication should apply through helsedata.no. Access to data sets requires approval from The Regional Committee for Medical and Health Research Ethics in Norway and an agreement with MoBa.

The UK Biobank phenotype and genetic data described here are publicly available to registered researchers through the UKB data access protocol. Information about registration for access to the data is available at: www.ukbiobank.ac.uk/enable-your-research/apply-for-access. This work was conducted using UK Biobank data, application number 9905.

All bona fide researchers can apply to use ALSPAC data for health-related research that is in the public interest. Information regarding the ALSPAC cohort and data access is available at www.bristol.ac.uk/alspac/researchers/our-data.

GWAS summary statistics can be obtained from the authors and will be made publicly available after peer review.