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

Smit RAJ., 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 S-H., 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 J-F., 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 A-E., Faul JD., Fernandez-Lopez J-C., 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 Y-L., Hofer E., Holliday E., Horn K., Hornsby WE., Hottenga J-J., Huang H., Huang J., Huerta-Chagoya A., Huo S., Hwang MY., Hwu C-M., 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 H-N., Kim YJ., Kleber ME., Knol MJ., Kurbasic A., Lauzon M., Le P., Lea R., Lee J-Y., Lee W-J., 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 L-P., 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 ERB., 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 PRHJ., 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 J-S., 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 J-H., Zhao W., Zhou W., Zimmermann ME., Zoledziewska M., 't Hart LM., Adair LS., Adams HHH., 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 Y-D., Chen Z., Cheng C-Y., 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 EJC., de Groot LCPGM., De Jager PL., de Kleijn DPV., de Silva HJ., Dedoussis GV., den Hollander AI., Du S., Easton DF., Eckardt K-U., Elders PJM., 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 SFA., Grarup N., Griffiths L., Gudnason V., Haiman C., Hakonarson H., Hansen T., Hartman CA., Hattersley AT., Hayward C., Heid IM., Heng C-K., Hengstenberg C., Herzig K-H., Hewitt AW., Hishigaki H., Hougaard DM., Hoyng CB., Huang PL., Huang W., Huang W-Y., Huffman JE., Hunt SC., Hutri N., Hveem K., Hyppönen E., Iacono WG., Ichihara S., Ikram MA., Isasi CR., Jarvelin M-R., Jin Z-B., Jöckel K-H., Jonas JB., Joshi PK., Jousilahti P., Jukema JW., Kähönen M., Kamatani Y., Kang KD., Kaprio J., Kardia SLR., Karpe F., Kato N., Kavousi M., Kee F., Kessler T., Khera AV., Khor CC., Kiemeney LALM., Kim B-J., Kim EK., Kim H-L., Kirchhof P., Kivimaki M., Koh W-P., 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 C-T., Liu J., Loeffler M., London B., Lu F., Lubitz SA., Mackey DA., Magnusson PKE., Manson JE., 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 CNA., Parra EJ., Pattaro C., Pedersen O., Pennell CE., Penninx BWJH., 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 WHH., Shoemaker MB., Shu X-O., 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 J-C., Thanaraj TA., Tönjes A., Tuomi T., Tuomilehto J., Tusié-Luna M-T., van Dam RM., van der Harst P., Van der Velde N., van Duijn CM., van Schoor NM., Vitart V., Vohl M-C., 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 PWF., Wong TY., Woo J-T., Wright AF., Xu H., Yajnik CS., Yang J., Yokota M., Yuan J-M., Zeggini E., Zemel BS., Zheng W., Zhu X., Zillikens MC., Zonderman AB., Zwart J-A., 23andMe Research Team ., DiscovEHR (DiscovEHR and MyCode Community Health Initiative) ., eMERGE (Electronic Medical Records and Genomics Network) ., GPC-UGR ., PRACTICAL Consortium ., Understanding Society Scientific Group ., VA Million Veteran Program ., Abecasis GR., Assimes TL., Auton A., Boehnke M., Chasman DI., Esko T., Stefansson K., Lettre G., Lindgren CM., Ng MCY., 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 RJF.

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.

DOI

10.1038/s41591-025-03827-z

Type

Journal article

Publication Date

2025-09-01T00:00:00+00:00

Volume

31

Pages

3151 - 3168

Total pages

17

Keywords

Adolescent, Adult, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Young Adult, Adiposity, Body Mass Index, Genetic Predisposition to Disease, Multifactorial Inheritance, Obesity, White People, Racial Groups

Permalink More information Close