Polygenic prediction of body mass index and obesity through the life course and across ancestries

Smit RA, Wade KH, Hui Q, Arias JD, Yin X, Christiansen MR, Yengo L, Preuss MH, Nakabuye M, Rocheleau G, Graham SE, Buchanan VL, Chittoor G, Graff M, Guindo-Martínez M, Lu Y, Marouli E, Sakaue S, Spracklen CN, Vedantam S, Wilson EP, Chen SH, Ferreira T, Ji Y, Karaderi T, Lüll K, Machado M, Malden DE, Medina-Gomez C, Moore A, Rüeger S, Akiyama M, Allison MA, Alvarez M, Andersen MK, Appadurai V, Arbeeva L, Bartell E, Bhaskar S, Bielak LF, Bis JC, Bollepalli S, Bork-Jensen J, Bradfield JP, Bradford Y, Brandl C, Braund PS, Brody JA, Broeckel U, Burgdorf KS, Cade BE, Cai Q, Camarda S, Campbell A, Cañadas-Garre M, Chai JF, Chesi A, Choi SH, Christofidou P, Couture C, Cuellar-Partida G, Danning R, Degenhardt F, Delgado GE, Delitala A, Demirkan A, Deng X, Dietl A, Dimitriou M, Dimitrov L, Dorajoo R, Eichelmann F, Eliasen AU, Engmann JE, Erdos MR, Fairhurst-Hunter Z, Farmaki AE, Faul JD, Fernandez-Lopez JC, Forer L, Frank M, Freitag-Wolf S, Fritsche LG, Fuchsberger C, Galesloot TE, Gao Y, Geller F, Giannakopoulou O, Giulianini F, Gjesing AP, Goel A, Gordon SD, Gorski M, Grove J, Guo X, Gustafsson S, Haessler J, Hansen TF, Havulinna AS, Haworth SJ, Heard-Costa N, Hemerich D, Highland HM, Hindy G, Ho YL, Hofer E, Holliday E, Horn K, Hornsby WE, Hottenga JJ, Huang H, Huang J, Huerta-Chagoya A, Huo S, Hwang MY, Hwu CM, Iha H, Ikeda DD, Isono M, Jackson AU, Jansen IE, Jiang Y, Johansson I, Jonsson A, Jørgensen T, Kalafati IP, Kanai M, Kanoni S, Kårhus LL, Kasturiratne A, Katsuya T, Kawaguchi T, Kember RL, Kentistou KA, Kim D, Kim HN, Kim YJ, Kleber ME, Knol MJ, Kurbasic A, Lauzon M, Le P, Lea R, Lee JY, Lee WJ, Leonard HL, Li H, Li SA, Li X, Li X, Liang J, Lin H, Lin K, Liu J, Liu X, Lo KS, Long J, Lores-Motta L, Luan J, Lyssenko V, Lyytikäinen LP, Mahajan A, Malik MZ, Mamakou V, Mangino M, Manichaikul A, Marten J, Mattheisen M, McDaid AF, Mei Q, Meiselbach H, Melendez TL, Milaneschi Y, Miller JE, Millwood IY, Mishra PP, Mitchell RE, Møllehave LT, Mononen N, Mucha S, Munz M, Mykkänen J, Nakatochi M, Nardone GG, Nelson CP, Nethander M, Nho CW, Nielsen AA, Nolte IM, Nongmaithem SS, Noordam R, Ntalla I, Nutile T, Pandit A, Pauper M, Petersen ER, Petersen LV, Piluso F, Polašek O, Poveda A, Pyarajan S, Raffield LM, Rakugi H, Ramirez J, Rasheed A, Raven D, Rayner NW, Riveros C, Rohde R, Ruggiero D, Ruotsalainen SE, Ryan KA, Sabater-Lleal M, Santin A, Saxena R, Scholz M, Shen B, Shi J, Shin JH, Sidore C, Sidorenko J, Sim X, Slieker RC, Smith AV, Smith JA, Smyth LJ, Southam L, Steinthorsdottir V, Sun L, Takeuchi F, Taylor KD, Tayo BO, Tcheandjieu C, Terzikhan N, Tesolin P, Teumer A, Theusch E, Thompson DJ, Thorleifsson G, Timmers PR, Trompet S, Turman C, Vaccargiu S, van der Laan SW, van der Most PJ, van Klinken JB, van Setten J, Verma SS, Verweij N, Veturi Y, Wang CA, Wang C, Wang JS, Wang L, Wang YX, Wang Z, Warren HR, Bin Wei W, Wen W, Wheeler WA, Wickremasinghe AR, Wielscher M, Winsvold BS, Wong A, Wuttke M, Xia R, Yamamoto K, Yang J, Yao J, Young H, Yousri NA, Yu L, Zeng L, Zhang W, Zhang X, Zhao JH, Zhao W, Zhou W, Zimmermann ME, Zoledziewska M, 't Hart LM, Adair LS, Adams HH, Aguilar-Salinas CA, Al-Mulla F, Arnett DK, Asselbergs FW, Åsvold BO, Attia J, Banas B, Bandinelli S, Beilin LJ, Bennett DA, Bergler T, Bharadwaj D, Biino G, Boerwinkle E, Böger CA, Borja JB, Bouchard C, Bowden DW, Brandslund I, Brumpton B, Buring JE, Caulfield MJ, Chambers JC, Chandak GR, Chanock SJ, Chaturvedi N, Ida Chen YD, Chen Z, Cheng CY, Cho YS, Christensen K, Christophersen IE, Ciullo M, Cole JW, Collins FS, Concas MP, Cooper RS, Cruz M, Cucca F, Cutler MJ, Damrauer SM, Dantoft TM, de Borst GJ, de Geus EJ, de Groot LC, De Jager PL, de Kleijn DP, de Silva HJ, Dedoussis GV, den Hollander AI, Du S, Easton DF, Eckardt KU, Elders PJ, Eliassen AH, Ellinor PT, Elmståhl S, Erdmann J, Evans MK, Fatkin D, Feenstra B, Feitosa MF, Ferrucci L, Florez JC, Ford I, Fornage M, Franke A, Franks PW, Freedman BI, Gieger C, Girotto G, Golightly YM, Gonzalez-Villalpando C, Gordon-Larsen P, Grallert H, Grant SF, Grarup N, Griffiths L, Gudnason V, Haiman C, Hakonarson H, Hansen T, Hartman CA, Hattersley AT, Hayward C, Heid IM, Heng CK, Hengstenberg C, Herzig KH, Hewitt AW, Hishigaki H, Hougaard DM, Hoyng CB, Huang PL, Huang W, Huang WY, Huffman JE, Hunt SC, Hutri N, Hveem K, Hyppönen E, Iacono WG, Ichihara S, Ikram MA, Isasi CR, Jarvelin MR, Jin ZB, Jöckel KH, Jonas JB, Joshi PK, Jousilahti P, Jukema JW, Kähönen M, Kamatani Y, Kang KD, Kaprio J, Kardia SL, Karpe F, Kato N, Kavousi M, Kee F, Kessler T, Khera AV, Khor CC, Kiemeney LA, Kim BJ, Kim EK, Kim HL, Kirchhof P, Kivimaki M, Koh WP, Koistinen HA, Kokkinos A, Kooner JS, Kooperberg C, Kovacs P, Kraaijeveld A, Kraft P, Krauss RM, Kumari M, Kutalik Z, Laakso M, Lange LA, Langenberg C, Launer LJ, Lee H, Lee NR, Lehtimäki T, Lemaitre RN, Li H, Li L, Lieb W, Lin X, Lind L, Linneberg A, Liu CT, Liu J, Loeffler M, London B, Lu F, Lubitz SA, Mackey DA, Magnusson PK, Manson JAE, Marcus GM, Marques Vidal P, Martin NG, März W, Matsuda F, McCarthy MI, McGarrah RW, McGue M, McKnight AJ, Medland SE, Mellström D, Metspalu A, Mitchell BD, Mitchell P, Mook-Kanamori DO, Mori TA, Morris AD, Mucci LA, Munroe PB, Nalls MA, Nazarian S, Nelson AE, Neville MJ, Newton-Cheh C, Nielsen CS, Niinikoski H, Nikus K, Nöthen MM, Ogunniyi A, Ohlsson C, Oldehinkel AJ, Orozco L, Pahkala K, Pajukanta P, Palmer CN, Parra EJ, Pattaro C, Pedersen O, Pennell CE, Penninx BW, Perusse L, Peters A, Peyser PA, Porteous DJ, Posthuma D, Power C, Pramstaller PP, Province MA, Psaty BM, Qi Q, Qu J, Rader DJ, Raitakari OT, Rallidis LS, Rao DC, Redline S, Reilly DF, Reiner AP, Rhee SY, Ridker PM, Rienstra M, Ripatti S, Ritchie MD, Rivadeneira F, Roden DM, Rosendaal FR, Rotter JI, Rudan I, Rutters F, Ryu S, Sabanayagam C, Salako B, Saleheen D, Salomaa V, Samani NJ, Sanghera DK, Sattar N, Schmidt B, Schmidt H, Schmidt R, Schulze MB, Schunkert H, Scott LJ, Scott RJ, Sever P, Sheu WH, Shoemaker MB, Shu XO, Simonsick EM, Sims M, Singleton AB, Sinner MF, Smith JG, Snieder H, Spector TD, Spedicati B, Stampfer MJ, Stark KJ, Strachan DP, Tabara Y, Tai ES, Tang H, Tardif JC, Thanaraj TA, Tönjes A, Tuomi T, Tuomilehto J, Tusié-Luna MT, van Dam RM, van der Harst P, Van der Velde N, van Duijn CM, van Schoor NM, Vitart V, Vohl MC, Völker U, Vollenweider P, Völzke H, Vrieze S, Wacher-Rodarte NH, Walker M, Wander GS, Wareham NJ, Watanabe RM, Watkins H, Weir DR, Werge TM, Widen E, Willemsen G, Willett WC, Wilson JF, Wilson PW, Wong TY, Woo JT, Wright AF, Xu H, Yajnik CS, Yang J, Yokota M, Yuan JM, Zeggini E, Zemel BS, Zheng W, Zhu X, Zillikens MC, Zonderman AB, Zwart JA, Abecasis GR, Assimes TL, Auton A, Boehnke M, Chasman DI, Esko T, Stefansson K, Lettre G, Lindgren CM, Ng MC, O'Donnell CJ, Thorsteinsdottir U, Visscher PM, Walters RG, Winkler TW, Wood AR, Deloukas P, Frayling TM, Justice AE, Kilpeläinen TO, Locke AE, Mohlke KL, North KE, Okada Y, Willer CJ, Young KL, Fatumo S, McCaffery JM, Timpson NJ, Hirschhorn JN, Sun YV, Berndt SI, Loos RJ (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 31

Pages Range: 3151-3168

Journal Issue: 9

DOI: 10.1038/s41591-025-03827-z

Abstract

Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.6% African ancestry, 14.4% American ancestry, 8.4% East Asian ancestry, 71.1% European ancestry and 1.5% South Asian ancestry) from the GIANT consortium and 23andMe, Inc., we developed ancestry-specific and multi-ancestry PGSs. The multi-ancestry score explained 17.6% of BMI variation among UK Biobank participants of European ancestry. For other populations, this ranged from 16% in East Asian-Americans to 2.2% in rural Ugandans. In the ALSPAC study, children with higher PGSs showed accelerated BMI gain from age 2.5 years to adolescence, with earlier adiposity rebound. Adding the PGS to predictors available at birth nearly doubled explained variance for BMI from age 5 onward (for example, from 11% to 21% at age 8). Up to age 5, adding the PGS to early-life BMI improved prediction of BMI at age 18 (for example, from 22% to 35% at age 5). Higher PGSs were associated with greater adult weight gain. In intensive lifestyle intervention trials, individuals with higher PGSs lost modestly more weight in the first year (0.55 kg per s.d.) but were more likely to regain it. Overall, these data show that PGSs have the potential to improve obesity prediction, particularly when implemented early in life.

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Lillebaelt Hospital / Sygehus Lillebælt Denmark (DK) Centre for Cellular and Molecular Biology (CSIR-CCMB) India (IN) University of Michigan United States (USA) (US) National Cancer Institute (NCI) United States (USA) (US) Universität zu Lübeck Germany (DE) Uppsala University Sweden (SE) University of Kelaniya Sri Lanka (LK) Universitätsklinikum Essen Germany (DE) Tampere University Hospital / Tampereen yliopistollinen sairaala (TAYS) Finland (FI) Finnish Institute for Molecular Medicine (FIMM) / Suomen Molekyylilääketieteen Instituutti Finland (FI) NUS Yong Loo Lin School of Medicine Singapore (SG) Universitätsklinikum Leipzig Germany (DE) Université Laval (UL) Canada (CA) University of Oxford United Kingdom (GB) Loyola University Chicago United States (USA) (US) Statens Serum Institut Denmark (DK) University of Utah United States (USA) (US) National Center for Global Health and Medicine (NCGM) Japan (JP) Korea National Institute of Health (KNIH) Korea, Republic of (KR) University of Pennsylvania (UPenn) United States (USA) (US) University of Toronto Canada (CA) University of Leicester United Kingdom (GB) University of Glasgow United Kingdom (GB) King’s College London United Kingdom (GB) National Institute on Aging (NIA) United States (USA) (US) Wake Forest University United States (USA) (US) University of Texas Health Science Center at Houston (UTHealth Houston) United States (USA) (US) Medical College of Wisconsin (MCW) United States (USA) (US) NTNU Trondheim - Norwegian University of Science and Technology Norway (NO) Deutsches Institut für Ernährungsforschung (DIfE) Germany (DE) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Universitätsklinikum Regensburg Germany (DE) University of Bergen / Universitetet i Bergen Norway (NO) Vejle Sygehus Denmark (DK) Leiden University Medical Center Netherlands (NL) IMS RIKEN Center for Integrative Medical Sciences Japan (JP) Capital University of Medical Sciences / 首都医科大学 China (CN) Consiglio Nazionale delle Ricerche (CNR) / National Research Council of Italy Italy (IT) St George's, University of London (SGUL) / St George's Hospital Medical School United Kingdom (GB) University of Copenhagen Denmark (DK) University of Tartu Estonia (EE) National and Kapodistrian University of Athens Greece (GR) Lundbeck Foundation Initiative for Integrative Psychiatric Research Denmark (DK) University of Washington United States (USA) (US) University of Queensland Australia (AU) U.S. Department of Veterans Affairs United States (USA) (US) Harvard University United States (USA) (US) University of California Los Angeles (UCLA) United States (USA) (US) Kyung Hee University Korea, Republic of (KR) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen Netherlands (NL) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) Harbor–UCLA Medical Center United States (USA) (US) Turku University Hospital / Turun yliopistollinen keskussairaala (TYKS) Finland (FI) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) Erasmus University Medical Center (MC) Netherlands (NL) 23andMe United States (USA) (US) University of North Carolina at Chapel Hill United States (USA) (US) Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Mexico (MX) Universität Regensburg Germany (DE) National Institute of Genomic Medicine / Instituto Nacional de Medicina Genómica (INMEGEN) Mexico (MX) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) University of Southern Denmark / Syddansk Universitet Denmark (DK) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Oulun Yliopisto / University of Oulo Finland (FI) Medizinische Universität Wien Austria (AT) Chinese National Human Genome Center (CHGB) / 国家人类基因组北方研究中心 China (CN) Università degli Studi di Sassari (UNISS) Italy (IT) University of Split / Sveučilište u Splitu Croatia (HR) Fondation Adolphe de Rothschild Hospital France (FR) Yonsei University Health System (YUHS) Korea, Republic of (KR) University of Virginia (UVA) United States (USA) (US) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) Sant Pau Institute for Biomedical Research (IIBSP) / Institut de Recerca de L’hospital de La Santa Creu i de Sant Pau Spain (ES) Icahn School of Medicine at Mount Sinai United States (USA) (US) Università degli Studi di Trieste Italy (IT) National Health Research Institutes (NHRI) / 國家衛生研究院 Taiwan (TW) deCODE genetics Iceland (IS) University of Cambridge United Kingdom (GB) Washington University in St. Louis United States (USA) (US) Deutsches Zentrum für Diabetesforschung e.V. (DZD) Germany (DE) Jichi Medical University / 自治医科大学 Japan (JP) Fimlab Laboratories Finland (FI) University College London (UCL) United Kingdom (GB) Nanjing Medical University / 南京医科大学 China (CN) Novo Nordisk Foundation / Novo Nordisk Fonden (NNF) Denmark (DK) University of Peloponnese Greece (GR) University of Maryland School of Pharmacy United States (USA) (US) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) Columbia University Irving Medical Center (CUIMC) United States (USA) (US) Lund University / Lunds universitet Sweden (SE) Christian-Albrechts-Universität zu Kiel Germany (DE) Weill Cornell Medicine-Qatar (WCM-Q) Qatar (QA) Keck School of Medicine of USC United States (USA) (US) University of Minnesota (UMN) United States (USA) (US) Peking University Health Science Center China (CN) Boston University United States (USA) (US) Karolinska Institute Sweden (SE) Norwegian Institute of Public Health (NIPH) / Folkehelseinstituttet Norway (NO) University of Edinburgh United Kingdom (GB) Queen Mary University of London United Kingdom (GB) Copenhagen University Hospital Denmark (DK) Case Western Reserve University United States (USA) (US) University of Mississippi Medical Center United States (USA) (US) Hunter Medical Research Institute (HMRI) Australia (AU) Universitätsklinikum Freiburg Germany (DE) University of South Australia Australia (AU) University of California San Francisco (UCSF) United States (USA) (US) Stanford University United States (USA) (US) Children's Hospital of Philadelphia United States (USA) (US) National University of Singapore (NUS) Singapore (SG) National Human Genome Research Institute (NHGRI) United States (USA) (US) Queensland University of Technology (QUT) Australia (AU) eurac research Italy (IT) Taichung Veterans General Hospital Taiwan (TW) Duke University United States (USA) (US) Universitätsklinikum Bonn Germany (DE) University of Newcastle (UoN) Australia (AU) Centro Medico Nacional Siglo XXI Mexico (MX) University of Connecticut (UConn) United States (USA) (US) Instituto Nacional de Salud Pública (INSP) / National Institute of Public Health Mexico (MX) Icelandic Heart Association (IHA) Iceland (IS) Institute of genetics and biophysics "Adriano Buzzati Traverso" (IGB) Italy (IT) Medizinische Universität Innsbruck Austria (AT) Rigshospitalet Denmark (DK) Medizinische Universität Graz Austria (AT) Louisiana State University United States (USA) (US) Otsuka Pharmaceutical Co., Ltd. / 大塚製薬株式会社 Japan (JP) University of Amsterdam Netherlands (NL) University of Exeter United Kingdom (GB) Institut de Cardiologie de Montréal Canada (CA) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) Germany (DE) Dayanand Medical College & Hospital India (IN) Singapore Eye Research Institute Singapore (SG) University of Oklahoma United States (USA) (US) Fred Hutchinson Cancer Research Center United States (USA) (US) Intermountain Healthcare United States (USA) (US) Wageningen University & Research Netherlands (NL) Southern University of Science and Technology China (CN) Taipei Veterans General Hospital / 台北榮民總醫院 Taiwan (TW) Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV) Switzerland (CH) Sahlgrenska University Hospital / Sahlgrenska Universitetssjukhuset Sweden (SE) University of Western Australia (UWA) Australia (AU) University of Dundee United Kingdom (GB) Nagoya University / 名古屋大学 Japan (JP) University of California, Riverside (UCR) United States (USA) (US) Geisinger Health System United States (USA) (US) RTI International United States (USA) (US) Harvard T.H. Chan School of Public Health United States (USA) (US) Queen's University United Kingdom (GB) Victor Chang Cardiac Research Institute Australia (AU) Albert Einstein College of Medicine United States (USA) (US) The Catholic University of Korea Incheon St. Mary's Hospital / 가톨릭대학교 인천성모병원 Korea, Republic of (KR) Genome Institute of Singapore Singapore (SG) Korea Institute of Science and Technology (KIST) / 한국과학기술연구원 Korea, Republic of (KR) University of Iowa United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) UPMC Hillman Cancer Center United States (USA) (US) Boston Children's Hospital United States (USA) (US) Huazhong University of Science & Technology China (CN) University of Massachusetts Medical School United States (USA) (US) Jawaharlal Nehru University (JNU) India (IN) University of Bristol United Kingdom (GB) Vanderbilt University United States (USA) (US) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) Sungkyunkwan University (SKKU) Korea, Republic of (KR) Université de Lausanne (UNIL) Switzerland (CH) Dasman Diabetes Institute Kuwait (KW) National Institute for Health and Welfare (THL) Finland (FI) University of San Carlos Philippines (PH) Massachusetts General Hospital United States (USA) (US) Merck & Co., Inc. / Merck Sharp & Dohme Corp (MSD) United States (USA) (US) Aarhus University Denmark (DK) Azienda USL Toscana Centro Italy (IT) Technische Universität München (TUM) Germany (DE) Ewha Womans University / 이화여자대학교 Korea, Republic of (KR) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Ealing Hospital NHS Trust United Kingdom (GB) University of Essex United Kingdom (GB) University of Eastern Finland Finland (FI) Great Ormond Street Hospital (GOSH) United Kingdom (GB) Brigham and Women's Hospital (BWH) United States (USA) (US) Shanghai Institute of Nutrition and Health (SINH) / 中国科学院 上海营养与健康研究院 China (CN) Umeå University Sweden (SE) Wenzhou Medical University / 温州医科大学 (WMU) China (CN) University of Sydney (USYD) Australia (AU) University of Ibadan Nigeria (NG) VA Palo Alto Health Care System United States (USA) (US) University of Tampere (UTA) / Tampereen yliopisto (Tay) Finland (FI) Hallym University Korea, Republic of (KR) Rush University United States (USA) (US) I.R.C.C.S. materno infantile Burlo Garofolo Italy (IT) Harokopio University / Χαροκόπειο Πανεπιστήμιο Greece (GR) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald Germany (DE) Pennsylvania State University (Penn State) United States (USA) (US) University of South Carolina United States (USA) (US) University of Tasmania (UTAS) Australia (AU) Veterans Health Administration (VHA) United States (USA) (US) Newcastle University United Kingdom (GB) University of Colorado Anschutz Medical Campus United States (USA) (US)

How to cite

APA:

Smit, R.A., Wade, K.H., Hui, Q., Arias, J.D., Yin, X., Christiansen, M.R.,... Loos, R.J. (2025). Polygenic prediction of body mass index and obesity through the life course and across ancestries. Nature Medicine, 31(9), 3151-3168. https://doi.org/10.1038/s41591-025-03827-z

MLA:

Smit, Roelof A.J., et al. "Polygenic prediction of body mass index and obesity through the life course and across ancestries." Nature Medicine 31.9 (2025): 3151-3168.

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