The role of common and rare genetic variation on adiposity across childhood.

The role of common and rare genetic variation on adiposity across childhood. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article The role of common and rare genetic variation on adiposity across childhood. Stefan Johansson, Katherine Kentistou, Jonas Sundfjord, Roya Karimi, and 27 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6649447/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract 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. Health sciences/Medical research/Genetics research Health sciences/Endocrinology/Endocrine system and metabolic diseases/Obesity Health sciences/Medical research/Paediatric research Full Text Additional Declarations Yes there is potential Competing Interest. 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. Supplementary Files Kentistou12May2025SupplementaryInformation.pdf Supplementary Information Kentistou12May2025SupplementaryData.xlsx Supplementary Tables 1-23 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6649447","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":460743730,"identity":"838bc51c-76ed-4cf6-b025-edeb4aeac479","order_by":0,"name":"Stefan 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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.","formattedTitle":"The role of common and rare genetic variation on adiposity across childhood.","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6649447/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6649447/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"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. 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