TY - JOUR
T1 - Polygenic prediction of body mass index and obesity through the life course and across ancestries
AU - 23andMe Research Team
AU - DiscovEHR (DiscovEHR and MyCode Community Health Initiative)
AU - eMERGE (Electronic Medical Records and Genomics Network)
AU - GPC-UGR
AU - The PRACTICAL Consortium
AU - Understanding Society Scientific group
AU - VA Million Veteran Program
AU - Smit, Roelof A.J.
AU - Wade, Kaitlin H.
AU - Hui, Qin
AU - Arias, Joshua D.
AU - Yin, Xianyong
AU - Christiansen, Malene R.
AU - Yengo, Loic
AU - Preuss, Michael H.
AU - Nakabuye, Mariam
AU - Rocheleau, Ghislain
AU - Graham, Sarah E.
AU - Buchanan, Victoria L.
AU - Chittoor, Geetha
AU - Graff, Marielisa
AU - Guindo-Martínez, Marta
AU - Lu, Yingchang
AU - Marouli, Eirini
AU - Sakaue, Saori
AU - Spracklen, Cassandra N.
AU - Vedantam, Sailaja
AU - Wilson, Emma P.
AU - Chen, Shyh Huei
AU - Ferreira, Teresa
AU - Ji, Yingjie
AU - Karaderi, Tugce
AU - Lüll, Kreete
AU - Machado, Moara
AU - Malden, Deborah E.
AU - Medina-Gomez, Carolina
AU - Moore, Amy
AU - Rüeger, Sina
AU - Akiyama, Masato
AU - Allison, Matthew A.
AU - Alvarez, Marcus
AU - Andersen, Mette K.
AU - Appadurai, Vivek
AU - Arbeeva, Liubov
AU - Bartell, Eric
AU - Bhaskar, Seema
AU - Bielak, Lawrence F.
AU - Bis, Joshua C.
AU - Bollepalli, Sailalitha
AU - Bork-Jensen, Jette
AU - Bradfield, Jonathan P.
AU - Bradford, Yuki
AU - Brandl, Caroline
AU - Braund, Peter S.
AU - Brody, Jennifer A.
AU - Broeckel, Ulrich
AU - Hottenga, Jouke Jan
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/9
Y1 - 2025/9
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105014329108
U2 - 10.1038/s41591-025-03827-z
DO - 10.1038/s41591-025-03827-z
M3 - Article
C2 - 40691366
AN - SCOPUS:105014329108
SN - 1078-8956
VL - 31
SP - 3151
EP - 3168
JO - Nature Medicine
JF - Nature Medicine
IS - 9
ER -