Nature Medicine | Volume 31 | September 2025 | 3151–3168 3151 nature medicine https://doi.org/10.1038/s41591-025-03827-zArticle Polygenic prediction of body mass index and obesity through the life course and across ancestries 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. Obesity is a major public health concern that causes or exacerbates many chronic diseases and leads to reduced life expectancy1–3. By 2035, more than half of the global population is projected to be living with overweight or obesity4. Although intensive lifestyle interventions (ILIs), bariatric surgery and weight loss medications are effective treatment options5,6, they are not without risk and likely to remain inaccessible to most people. Thus, preventing obesity remains paramount. In contrast to many other chronic conditions, obesity often mani- fests itself during childhood and tends to persist into adulthood7–9. Therefore, predictors available in early life, such as genetic variants, which are fixed at conception, could be of particular value. In recent years, PGSs that capture an individual’s inherited polygenic susceptibil- ity to a trait or disease have shown great promise in enhancing disease risk prediction and population screening10,11. However, it remains unclear how, when and under what circumstances PGSs for obesity might demonstrate utility for risk prediction. The widely used PGS for obesity by Khera et al.12, based on a genome-wide association study (GWAS) of BMI in over 339,000 peo- ple of predominantly European ancestry, explains approximately 8.5% of the variation in BMI in adults. However, as a PGS based on one ancestry population may have weak transferability to other ancestry populations13,14, there is a growing recognition that PGSs that represent a broad range of populations are needed to ensure quality healthcare for all15. By leveraging the results of the largest GWAS meta-analyses for BMI from the Genetic Investigation of ANthropometric Traits Received: 31 October 2024 Accepted: 6 June 2025 Published online: 21 July 2025 Check for updates  e-mail: ruth.loos@sund.ku.dk A list of authors and their affiliations appears at the end of the paper Nature Medicine | Volume 31 | September 2025 | 3151–3168 3152 Article https://doi.org/10.1038/s41591-025-03827-z diversity among participants (see Supplementary Tables 2 and 3 for study-specific population descriptors). Using PRS-CS(x)16,17, we created ancestry-specific and multi-ancestry PGSs leveraging up to 1.3 million common variants. We first identified the optimal genome-wide shrinkage parameter and linear combination weights for PRS-CS(x) that achieved the highest explained variance for BMI in six ancestry subpopulations of the UK Biobank (UKBB)18, including individuals of Middle Eastern-like ancestry (MID). For the EUR-tuning population, we selected a random subset of 20,000 unrelated indi- viduals (Methods and Supplementary Tables 3 and 4). Overall, a multi-ancestry PGS consisting of a linear combina- tion of five ancestry-specific PGSs (PGSLC) was the best-performing score (Methods, Fig. 2a and Supplementary Tables 5 and 6). In abso- lute terms, the explained variance of this multi-ancestry PGS for BMI ranged between 7.2% (AFR) and 17.5% (EUR), with a median of 14.0% (Fig. 2a and Supplementary Table 5). The multi-ancestry PGS resulted in a higher explained variance than the PGSs trained only with GWAS summary statistics most closely corresponding to the target population (‘ancestry-matched’) (Supplementary Table 5). This was particularly evident for the populations of African-like and Central/South Asian-like ancestry (2.6-fold and 2.8-fold increase, respectively), consistent with the smaller GWAS sample sizes avail- able for these populations. The performance of a PGS consisting of near-independent, genome-wide significant variants from the overall multi-ancestry GWAS meta-analysis was generally intermediate to that (GIANT) consortium and 23andMe, we derived ancestry-specific and multi-ancestry PGSs for BMI and obesity to examine their performance (1) across diverse adult populations, (2) across childhood and adoles- cence and (3) in the context of ILIs aimed at weight loss (Fig. 1). Results Selecting the best-performing PGS To develop a PGS for BMI, we used GWAS meta-analysis summary statistics for BMI from over 200 studies from the GIANT consor- tium and 23andMe (Supplementary Tables 1 and 2), excluding eight studies used for tuning parameters and for testing performance (Methods). The GWAS summary statistics included contributions from over 5.1 million people of diverse populations based on a com- bination of self-identified ethnicity and genetic similarity: 71.1% of participants were of predominantly European ancestry; 14.4% were of Hispanic ethnicity with typically admixed ancestries; 8.4% were of predominantly East Asian ancestry; 4.6% were of predominantly African ancestry (primarily admixed African American popula- tions); and 1.5% were of predominantly South Asian ancestry. We refer to these groups, and to the most closely aligning, geneti- cally inferred population groups from our PGS tuning and testing studies, as being of European-like ancestry (EUR), East Asian-like ancestry (EAS), American-like ancestry (AMR), African-like ances- try (AFR) and South Asian-like ancestry (SAS), respectively, while acknowledging that these groupings oversimplify the actual genetic Validation in adulthood UKBB MVP BioMe Biobank GPC-UGR AFR AMR EAS EUR SAS AFR AMR EAS EUR SAS PRS-CS PRS-CSx Global shrinkage parameter (Φ) Φ (1) β1 × PGSAFR + β2 × PGSAMR + β3 × PGSEAS + β4 × PGSEUR + β5 × PGSSAS (2) Φ Input Method Tuning 'meta' 'Linear combination' UKBB AFR 6.2k; AMR 0.9k; EAS 2.7k; EUR 20k; SAS 8k; MID 1.6k Select best PGS based on explained variance for BMI Testing Childhood and adolescence ALSPAC Weight change due to ILI DPP trial Look AHEAD trial GWAS meta-analyses for BMI from GIANT consortium and 23andMe African nmax 239k Hispanic/American nmax 735k European nmax 3.64M East Asian nmax 430k South Asian nmax 75k In of Multi-ancestryAncestry-specific (e.g., AFR) From early adulthood to middle life PLCO Cancer Screening Trial Fig. 1 | Study overview. PGSs were constructed using ancestry-specific GWAS summary statistics, using ancestry-specific (PRS-CS) and ancestry-combined (PRS-CSx) approaches. Tuning of the global shrinkage parameter (ϕ) and optimal weights for the linear combination version of PRS-CSx was performed in the UKBB. The best-performing score across multiple ancestries was taken forward to independent validation studies (linear combination version of PRS-CSx with ϕ 1 × 10−2). Population descriptors shown in the figure reflect a combination of self-identified ethnicity and genetic similarity. Created in BioRender: Smit, R. (2025): https://BioRender.com/fglrflj. Nature Medicine | Volume 31 | September 2025 | 3151–3168 3153 Article https://doi.org/10.1038/s41591-025-03827-z 7.2 15.9 12.4 12.6 15.3 17.5 African Admixed American Middle Eastern East Asian Central/South Asian European 0 5 10 15 20 In cr em en ta l e xp la in ed v ar ia nc e (% ) Ancestry-matched PGS. Genome-wide significant SNPs Multi-ancestral PGSLC 5.1 6.3 2.2 9.910.5 10.1 16 13.7 17.6 12.9 13.4 AFR AMR AS EAS SAS EUR BioMeBioMe GPC-UGR MVP MVP MVP BioMe BioMe BioMe MVP UKBB 0 5 10 15 20 In cr em en ta l e xp la in ed v ar ia nc e (% ) PGSKhera GSLC –0.5 0 0.5 1 2 3 4 5 6 7 8 9 10 PGSLC decile Tr ai t i n s.d . u ni ts Women Men BF% BMI WHR a b c Fig. 2 | Explained variance for BMI in adult populations. a, Explained variance for BMI in UKBB tuning populations, defined as adjusted R2 of the rank-based inverse-normal transformed BMI (by sex) predicted by the PGS, incremental to age, genotyping array and ancestry principal components. Error bars represent 95% confidence intervals (CIs) from 1,000 bootstrap resamples. The ancestry- matched PGS is the best-performing PRS-CS score using ancestry-specific GWAS summary statistics. The genome-wide significant score reflects a weighted sum of near-independent SNPs obtained from approximate COJO multi-SNP analyses of a fixed-effect meta-analysis of all contributing GWASs. The multi- ancestral PGSLC reflects the best-performing PRS-CSx score consisting of a linear combination of five ancestry-specific scores, with weights being specific to the validation population (for example, AFR). Population labels follow PAN-UKBB assignment of genetically determined ancestry. Sample sizes (distinct individuals): African 6,154; Admixed American 971; Middle Eastern 1,553; East Asian 2,660; Central/South Asian 8,005; European 20,000. b, Explained variance for BMI within validation populations, comparing the multi-ancestry PGSLC to a previously published score (PGSKhera) based on a smaller BMI GWAS meta-analysis. Same R2 definition and CI estimation as in a. Population descriptors reflect a combination of self-identified ethnicity and genetic similarity. For the MVP’s non-Hispanic Asian (AS) group, the result shown is for the PGSLC using the linear combination weights derived from UKBB-EAS. Sample sizes (distinct individuals), from left to right: AFR 12,263, 2,332, 18,701; AMR 10,281, 8,096; AS 4,201; EAS 1,359; SAS 1,177; EUR 13,673, 69,828, 340,224. c, Separation in BMI, body fat percentage (BF%) and waist-to-hip ratio (WHR) across deciles of the PGSLC within the validation subset of the UKBB participants of European-like ancestry (n ~ 340,000). All traits were rank-based inverse- normal transformed by sex. Nature Medicine | Volume 31 | September 2025 | 3151–3168 3154 Article https://doi.org/10.1038/s41591-025-03827-z of the ancestry-matched and multi-ancestry PGSs, with the exception of populations of East Asian-like and European-like ancestry, in whom it performed worse than either (Fig. 2a). Predicting prevalent obesity in adulthood Having tuned parameters in a subset of the UKBB, we took PGSLC for- ward to independent validation populations, estimating the predic- tion accuracy for BMI and obesity in 482,135 participants from the UKBB, the Million Veteran Program (MVP)19,20, the BioMe Biobank21 and the Uganda General Population Cohort (GPC-UGR)22. Individu- als were grouped by population group (AMR 22,612, AFR 29,454, EAS 1,617, EUR 423,420, SAS 1,164 and non-Hispanic Asian (AS) 4,201) (MVP-specific population label) (Methods and Supplementary Tables 3 and 4). The prevalence of obesity varied substantially across popula- tions and cohorts, with those having obesity class I or higher (that is, BMI ≥ 30 kg m−2 in AFR, AMR and EUR populations and BMI ≥ 27.5 kg m−2 for Asian-like ancestry populations23) ranging from 4.3% for the GPC-UGR to more than 45% for all ancestry subgroups in the MVP and mean BMI ranging from 22.2 kg m−2 to 30.6 kg m2 (Extended Data Fig. 1 and Supplementary Table 4). The performance of the PGSLC was highest in individuals of European-like ancestry from the UKBB, with an explained variance of 17.6%. A pronounced lower performance was seen for populations with greater proportions of African-like ancestry, with the explained variance being 6.3% and 5.1% in African American populations (from BioMe and MVP, respectively) and 2.2% in the GPC-UGR population from rural southwestern Uganda (Fig. 2b and Supplementary Table 7). Overall, we observed a median explained variance of 10.3% across our testing populations. Compared to the previously reported PGS by Khera et al. (PGSKhera) 12, which was based on a smaller BMI GWAS of up to 339,224 individuals of primarily European ancestry24, we observed a 1.9–2.6-fold increase in explained variance for BMI (Fig. 2b). Within the UKBB participants of European-like ancestry, the explained variance was marginally higher in males than in females (males: 17.9%; females: 17.3%) and higher in younger compared to 0 20 40 60 0 25 50 75 100 1% groups of PGS In di vi du al s w ith B M I ≥ 3 0 kg m –2 (% ) PGSKhera PGSLC 0.57 0.65 0.71 0.72 0.58 0.6 0.63 0.66 0.54 0.63 0.68 0.69 0.57 0.68 0.74 0.76 0.58 0.62 0.68 0.69 0.55 0.68 0.74 0.75 0.6 0.61 0.64 0.69 0.56 0.65 0.7 0.71 0.54 0.76 0.82 0.82 0.57 0.65 0.75 0.76 0.55 0.72 0.78 0.79 0.63 0.62 0.67 0.72 0.6 0.68 0.73 0.75 0.57 0.63 0.68 0.68 0.58 0.57 0.61 0.63 0.56 0.61 0.65 0.66 0.54 0.63 0.68 0.68 0.58 0.64 0.7 0.71 0.59 0.58 0.62 0.65 0.55 0.62 0.66 0.67 0.57 0.66 0.71 0.72 0.59 0.66 0.72 0.73 0.59 0.6 0.64 0.66 0.55 0.64 0.69 0.7 0.57 0.7 0.75 0.76 0.61 0.65 0.72 0.73 0.64 0.69 0.77 0.79 0.69 0.73 0.81 0.83 BioMe MVP UKBB O besity class I or higher O besity class II or higher O besity class III or higher Ag e+ se x PG S K he ra PG S L C Ag e+ se x+ PG S L C Ag e+ se x PG S K he ra PG S L C Ag e+ se x+ PG S L C Ag e+ se x+ C BS 10 PG S K he ra PG S L C Ag e+ se x+ C BS 10 +P G S L C EUR SAS EAS AS AMR AFR EUR SAS EAS AS AMR AFR EUR AS AMR AFR AUC 0.5 0.6 0.7 0.8 0.9 a b c AFR AMR AS EAS SAS EUR BioMe GPC-UGR MVP BioMe MVP MVP BioMe BioMe BioMe MVP UKBB 1.0 1.2 1.5 2.0 2.5 3.0 O dd s ra tio p er s .d . PGSKhera PGSLC Fig. 3 | Prediction of prevalent obesity outcomes in adults. a, Separation in prevalence of obesity (BMI ≥ 30 kg m−2) across 1% groups of PGSKhera and PGSLC within the validation subset of the UKBB participants of European-like ancestry (n ~ 340,000), with reference lines for the bottom and top 1% groups. Error bars show 95% confidence intervals (CIs) based on the normal approximation to the binomial distribution. The horizontal lines correspond to the average prevalence (black, dotted) and the prevalence of obesity within the top and bottom 1% of PGSKhera and PGSLC (red and blue, respectively). b, Odds ratios with 95% CIs for prevalent obesity class I or higher, per s.d. of PGSKhera and PGSLC, adjusted for age, sex, principal components of ancestry and genotyping array. All PGSs were standardized using the mean and s.d. of the PGS within individuals who did not have obesity class I or higher, to account for differences in prevalence across validation populations. Sample sizes (distinct individuals), from left to right: AFR 12,263, 2,332, 18,701; AMR 10,281, 8,096; AS 4,201; EAS 1,359; SAS 1,177; EUR 13,673, 69,828, 340,224. c, AUC classification of prevalent obesity outcomes in the BioMe Biobank, the MVP and the UKBB. Models including PGSs (included as a continuous predictor) additionally include principal components of ancestry. CBS10, self-reported comparative body size at age 10 years. Restricted to estimates where the number of individuals with the obesity outcome was at least 50. Nature Medicine | Volume 31 | September 2025 | 3151–3168 3155 Article https://doi.org/10.1038/s41591-025-03827-z older participants (≤50 years: 18.8%; >50 years: 17.0%) (Supplemen- tary Table 8), both directionally consistent with sex-specific and age-specific genetic differences previously observed for BMI25,26. Within this same cohort, an s.d. increase of PGSLC was associated with a 1.98 kg m−2 higher BMI (equivalent to 5.7 kg of body weight for a 1.7-m tall person) (Supplementary Table 9). The corresponding mean separa- tion across deciles of PGSLC was less pronounced for body fat percent- age and waist-to-hip ratio compared to BMI (Fig. 2c), revealing that the score does not equally capture differences in body composition. We further evaluated the overall performance and discrimina- tion of the PGS for prevalent obesity. Among European-like ances- try population groups, the PGSLC showed an improved capacity to differentiate between participants with and without obesity (BMI ≥ 30 kg m−2) compared to PGSKhera. Specifically, the prevalence in the top 1% of the PGSLC was 69.5% versus 54.9% for PGSKhera and, in the bottom 1%, 1.7% versus 5.1%, respectively (Fig. 3a and Extended Data Fig. 2). Across populations, an s.d. increase in PGSLC was associ- ated with a median 1.9–2.6-fold increase in odds of obesity class I or higher (Fig. 3b). We observed larger effects for more severe obesity (Extended Data Fig. 3 and Supplementary Tables 9 and 10). The area under the receiver operating characteristic curve (AUC) similarly increased with the severity of obesity and neared 0.80 for severe obesity in multiple populations (Fig. 3c). The AUC for PGSLC on its own was consistently larger than those for age and sex, PGSKhera and within the UKBB self-reported comparative body size at age 10 (Fig. 3c and Supplementary Table 11). 0 0.2 0.4 0 5 10 15 20 25 Age (years) PG S e ec t s iz e (tr ai t s .d . p er P G S s. d. ) BMI Height 15 20 25 0 5 10 15 20 25 Age (years) BM I ( kg m –2 ) PGS category Bottom 10% Middle 80% Top 10% a b Outcome: BMI at given timepoint Outcome: BMI at 18 years Predictors: birthweight, maternal education, pre-pregnancy maternal BMI, maternal age at date of birth and household social status Predictor: BMI at current timepoint Bir th 3 y ea rs 5 y ea rs 8 y ea rs 11 ye ars 15 ye ars 1 y ea r 2 y ea rs 3 y ea rs 4 y ea rs 5 y ea rs 8 y ea rs 0 10 20 30 40 50 Ex pl ai ne d va ria nc e (% ) Excluding PGS Including PGS c Fig. 4 | PGSLC performance during childhood and adolescence. a, Repeated cross-sectional linear regression associations of standardized PGSLC with BMI and height, with both standardized within sample by sex and timepoint. Data are presented as regression coefficient with 95% confidence interval (CI). Ponderal index was used instead of BMI at birth. Associations were adjusted for age and principal components of ancestry. Sample sizes, based on repeated measurements, from left to right, for BMI: 4,740, 638, 847, 814, 769, 41, 732, 729, 725, 720, 699, 5,816, 4,863, 5,570, 5,368, 5,187, 4,910, 4,556, 4,024, 3,603, 2,780; and height: 4,802, 638, 847, 814, 771, 741, 734, 729, 726, 723, 701, 5,820, 5,160, 5,572, 5,379, 5,188, 4,956, 4,561, 4,032, 3,606, 2,782. b, Sequentially plotted mean BMI trajectories from the age of 4 months to 24 years with knot points from linear spline multilevel models, accounting for sex and principal components of ancestry, of PGSLC (bottom 10%, middle 80%, top 10%). c, Contribution of PGSLC to explained variance (adjusted R 2) for BMI, rank-based inverse-normal transformed by sex and timepoint. Ponderal index was used instead of BMI at birth. Data are presented as R2 values computed from the original dataset, with error bars representing 95% confidence intervals (2.5th–97.5th percentiles) estimated from 1,000 bootstrap resamples. Predictors available at birth were birthweight, maternal education, pre-pregnancy maternal BMI, maternal age at date of birth and household social status. The left panel shows explained variance for BMI at the timepoint shown on the x axis. In contrast, the right panel shows explained variance for BMI measured at 18 years, with early-life BMI measurement shown on the x axis used as predictors. Sample sizes, based on repeated measurements, from left to right: 3,800, 839, 714, 1,192, 4,062, 3,044, 940, 594, 737, 725, 890, 3,310. Nature Medicine | Volume 31 | September 2025 | 3151–3168 3156 Article https://doi.org/10.1038/s41591-025-03827-z After an ancestry adjustment (Methods and Extended Data Fig. 4), the median odds ratio for obesity class I or higher across BioMe’s popu- lation groups was 3.6 for those in the top 10% of PGSLC (compared to bottom 90%) and 4.1 for the top 5% (versus those in the bottom 95%) (Supplementary Table 12), with greater separation between these two tail estimates for European-like and Asian-like ancestry groups. Childhood and adolescence We investigated whether PGSLC has predictive value at an early age within the Avon Longitudinal Study of Parents and Children (ALSPAC), a geographically homogeneous prospective birth cohort from the southwest of England with follow-up until early adulthood (Methods and Supplementary Table 3)27–29. Repeated cross-sectional associa- tions with BMI showed small effects for PGSLC soon after birth with much stronger effects emerging in early childhood, from 0.12 s.d. per s.d. of PGSLC at 12 months to nearly quadruple that size (0.45 s.d. per s.d. of PGSLC) by age 12 years, after which effects plateaued (Fig. 4a). The PGS was also associated, albeit less strongly, with height in early childhood with effects increasing until age 12 years, after which they returned to zero by mid-adolescence, suggesting that genetic predis- position for higher BMI early in life promotes increased body size in general, including postnatal linear growth, but that this early growth does not translate into differences in height after puberty (Extended Data Fig. 5). This is in line with childhood overweight and obesity’s known associations with earlier pubertal timing30. Over time, BMI in children with a higher genetic predisposition (PGS ≥10th percentile) increased at a faster rate than those with a lower genetic predisposi- tion, most evident after age 2.5 years (Methods, Fig. 4b and Supple- mentary Table 13). Both boys and girls with a very early age of adiposity rebound (≤43 months), a well-established predictor of future obesity risk31, had a higher mean PGS than those with later ages of adiposity rebound (Supplementary Table 14). We then examined whether the PGS adds predictive value over and above clinically available predictors of obesity. When added to predictors that are measurable at birth (birthweight, maternal educa- tion, pre-pregnancy maternal BMI, maternal age at date of birth and household social status), the PGS showed no clear added value for predicting ponderal index at birth or BMI at ages 3 years and 5 years (Methods and Fig. 4c, left panel). However, for predicting BMI at later ages (8, 11 and 15 years), the contribution of the predictors at birth plateaued, whereas inclusion of the PGS roughly doubled the total explained variance from 11% to 21% at age 8 and from 13% to 26% at age 15 (Fig. 4c, left panel). For the prediction of BMI in early adulthood, the contribution of the PGS especially shines through in the first few years after birth. BMI measured at age 8 explained 44% of the variation in BMI at age 18, and adding the PGS to the prediction model only raised this to 49%. In contrast, at younger ages, adding the PGS to measured BMI led to larger relative increases in the explained variance for BMI at 18 years, from 1.5-fold at age 5 (from 22% to 35%) to more than three-fold (from 8% to 26%) at 1 year of age (Fig. 4c, right panel, and Supplementary Table 15). From early adulthood to middle life Within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial (Methods)32, both males and females with a higher PGS experienced a greater change in self-reported weight and BMI between age 20 and age 50. Across populations, the per-5-year change per s.d. in PGSLC was consistently larger for females than for males (median of 0.35 kg for females versus 0.21 kg for males and 0.14 kg m−2 0.78 0.79 0.78 0.81 0.87 0.88 0.82 0.84 0.71 0.74 0.69 0.73 0.80 0.82 0.74 0.78 0.73 0.74 0.72 0.76 0.77 0.79 0.72 0.74 0.82 0.83 0.90 0.91 0.86 0.88 0.73 0.75 0.78 0.83 0.81 0.82 0.79 0.80 0.81 0.82 0.90 0.91 0.89 0.91 0.80 0.85 0.85 0.86 0.86 0.87 All Without overweight at 20y Overweight or obesity at 20y O besity class I or higher at 50y O besity class II or higher at 50y O besity class III or higher at 50y Bi rt h ye ar + s ex + BM I a t 2 0y + P C s M 1 + P G S L C Bi rt h ye ar + s ex + BM I a t 2 0y + P C s M 1 + P G S L C Bi rt h ye ar + s ex + BM I a t 2 0y + P C s M 1 + P G S L C European East Asian Hispanic African/African American European East Asian African/African American European African/African American AUC 0.5 0.6 0.7 0.8 0.9 Fig. 5 | AUC for obesity classification at age 50, stratified by having overweight or obesity at age 20. Analyses performed within the PLCO Cancer Screening Trial. Restricted to estimates where the number of individuals with the obesity outcome was at least 50. Population descriptors were provided by the PLCO investigators and reflect genetically determined ancestry using Genetic Relationship and Fingerprinting (GRAF). PCs, principal components; y, years; M1, model with birth year, sex, BMI at 20y, and PCs. Nature Medicine | Volume 31 | September 2025 | 3151–3168 3157 Article https://doi.org/10.1038/s41591-025-03827-z versus 0.07 kg m−2 for BMI), also when corrected for initial weight or BMI (Supplementary Table 16). The addition of the PGS to a model with birth year, sex and BMI at age 20 was associated with modest increases in discriminative ability for predicting obesity at age 50 (incremental AUC ranged from 0.01 to 0.03; Fig. 5). There was evidence of statistical interaction between the PGS and BMI at age 20 for obesity at age 50 (Methods and Sup- plementary Table 17), which translated into a larger incremental AUC of the PGS for those who did not have overweight or obesity at age 20 (range, 0.02–0.05; Fig. 5), without strong evidence of sex specificity (Extended Data Fig. 6). Response to ILIs Lifestyle modification remains a cornerstone of weight management, with multicomponent ILIs having shown success in achieving clinically relevant weight loss33. However, ILIs require substantial, sustained investment from both healthcare providers and patients, with large vari- ation in weight loss and unintentional weight regain being common34–36. To examine whether polygenic predisposition to obesity might modify the effectiveness of such interventions, we examined whether the PGS was associated with weight loss during the first year of an ILI, and with weight regain thereafter, in two randomized controlled trials with simi- lar intervention arms aimed at achieving 7% weight loss: the Diabetes Prevention Program (DPP33) and the Look AHEAD (Action for Health in Diabetes37) studies (Methods). Among 3,909 participants (Supplementary Table 4), individuals with a higher PGSLC lost more weight during the first year in response to the ILI compared to the control group (−0.55 kg per s.d. in PGS, 95% confidence interval: −0.94 to −0.16) (Fig. 6), when adjusting for starting weight. In addition, among those who lost at least 3% of their baseline weight during the first year, a higher PGS was associated with more weight regain in the following years (up to 3 years) (0.48 kg per PGS s.d., 95% confidence interval: 0.00–0.95) (Fig. 6). These findings were directionally consistent across (self-)reported population groups. Discussion We used GWAS summary statistics from the GIANT consortium and 23andMe, encompassing over 5.1 million people, to cre- ate ancestry-specific and multi-ancestry PGSs capturing genetic predisposition to weight gain and obesity. Our multi-ancestry PGS more than doubled the explained variance for BMI compared to the widely used PGS by Khera et al.12. Additionally, we demonstrate the potential added value of the PGS in two distinct clinical applications: predicting adult BMI at an early age and weight change in response to ILIs. Across diverse populations, the increases in explained variance for BMI were accompanied by substantial improvements in effect sizes and discrimination metrics for obesity, with the PGSs’ stan- dalone AUC nearing 0.80 for severe obesity. Consistent with other polygenic traits, our results underscore the importance of training sample size in driving PGS performance improvements. Nonetheless, our results also show diminishing returns of sample size increases, as has been observed for other polygenic traits38, with a 15-fold increase in total sample size (compared to PGSKhera, ~10-fold in EUR alone) leading to a 2–3-fold increase in prediction accuracy. We leveraged PRS-CSx’s unique ability to integrate GWAS summary statistics from all five broad ancestry population groups from the meta-analyses from GIANT and 23andMe17. However, recent Bayesian methods have shown promising results with smaller sample sizes by including addi- tional variants and functional annotation, meriting consideration for future comparisons39,40. Although our results highlight the value of multi-ancestry PGS to increase PGS performance, a considerable performance gap persists for populations with substantial African-like genetic ancestry compared to other populations. This discrepancy is likely due to the underrepresentation of individuals with African-like ancestry in the training GWAS, particularly from continental Africa41, and differences in minor allele frequency (MAF) and linkage disequi- librium (LD) patterns42,43. The lower performance of the PGS in the GPC-UGR is in line with those seen therein for PGSs for other traits and the limited transferability of PGS performance between African ances- try populations, reflecting genetic and environmental differences as well as their interactions22,44–47, emphasising that much remains to be done to improve the performance of genetic risk prediction across the genetically diverse populations within Africa. For example, it remains unclear whether a finer classification of broad ancestry groups in GWAS meta-analyses and PGS development could improve downstream PGS generalizability, especially given the dominant role of GWAS sam- ple size. Given the observed performance gap, careful implementa- tion of the score is essential to avoid potentially introducing public Black Hispanic White All DPP LA DPP LA DPP LA DPP LA –2 –1 0 1 2 kg –0.41 (–1.27; 0.44) –0.47 (–1.27; 0.34) –0.60 (–1.11; –0.08) –0.55 (–0.94; –0.16) –0.90 (–2.21; 0.40) –0.05 (–1.18; 1.07) –0.00 (–1.44; 1.43) –0.68 (–1.66; 0.29) –0.87 (–1.72; –0.01) –0.44 (–1.09; 0.20) –0.73 (–1.36; –0.09) –0.44 (–0.93; 0.05) 95% CI Weight change during first year (kg) per PGS s.d. Black Hispanic White All DPP LA DPP LA DPP LA DPP LA –2 –1 0 1 2 Kg 0.75 (–0.34; 1.83) 0.37 (–0.24; 0.98) 0.48 ( 0.00; 0.95) 1.17 (–0.51; 2.84) –0.67 (–2.59; 1.25) 0.37 (–0.89; 1.63) 0.46 (–1.07; 1.99) 1.04 (–0.49; 2.57) 0.55 (–0.42; 1.53) 0.25 (–0.53; 1.03) 0.60 (–0.13; 1.33) 0.39 (–0.24; 1.01) 95% CI Weight change after first year (kg) per PGS s.d., in those who lost 3% during first year Fig. 6 | Impact of PGSLC on weight change due to ILIs. Interaction effect between PGSLC and trial arm (ILI versus comparison arm) for weight change within the first year of follow-up (left) and weight change after the first year in the subset of individuals who had lost ≥3% of baseline weight at year 1 (right). Data are presented as study-specific and study-combined interaction regression coefficients (with 95% confidence interval (CI)), pooled through inverse- variance weighted fixed-effect meta-analysis. Weight change was assessed by using weight at follow-up timepoint(s) as outcome in the linear mixed models, adjusting for initial weight (baseline or year 1, respectively). LA, Look AHEAD. Population descriptors reflect race and ethnicity, as reported by dbGAP variable phv00201855.v2.p1 (DPP) or self-report by participants (LA). Study-specific sample sizes (distinct individuals, with pooled sample sizes for ‘All’), from top to bottom, for forest plot on the left: 295, 374, 251, 428, 839, 1,722, 1,385, 2,524; and on the right: 118, 186, 128, 233, 428, 951, 674, 1,370. Nature Medicine | Volume 31 | September 2025 | 3151–3168 3158 Article https://doi.org/10.1038/s41591-025-03827-z health disparities. For example, establishing a standardized ancestry threshold14,48 may improve the accuracy of population-specific risk stratification and ensure that the score is returned only in populations where it meets an acceptable performance threshold. Within ALSPAC, the PGS—which was developed for adult BMI— already shows an effect on BMI early in life. Effect sizes rapidly increased with age and were accompanied by clear divergence of BMI trajectories throughout childhood and adolescence. As a result, the PGS showed added value beyond clinically available predictors assessed at birth for predicting BMI measured after age 5. This is in line with previous research on the dynamic relationship between genetic variation and adiposity in early life12,49,50. Particularly elucidating are the observa- tions from the Norwegian Mother, Father and Child Cohort Study (MoBa) with repeated measurements across narrow age windows51. They show that BMI has a rapidly changing genetic architecture during the first 8 years of life with a ‘late rise’ cluster of variants, emerging in late childhood, which show limited association before the adiposity rebound but have persistent effects on BMI into adult life51. This also explains why our PGS shows its value for predicting adult BMI during the earliest years of life, up to age 5, when measured BMI has limited value as a predictor. With a growing number of obesity prevention tri- als commencing in early life52,53, our results provide important context at what age(s) PGSs for obesity, potentially in tandem with PGSs of obesity-related complications, could be considered promising candi- date predictors to help guide risk stratification and the implementation of such interventions. In the PLCO study, a higher PGS was associated with weight gain over a 30-year period from early adulthood to midlife. Additionally, for individuals aged 20, knowing their PGS modestly improved the prediction of obesity at age 50, more so for those without overweight or obesity at age 20. This suggests that particularly individuals with an early adulthood BMI below their genetically predicted BMI are at risk of gaining weight to match their innate predisposition. Our findings are consistent with those from the CARDIA study54, showing that PGSs for obesity only marginally improve the prediction of midlife BMI when combined with early adulthood BMI measurements, contrasting with its predictive value in early life. Analyzing clinical trial data of ILIs, we observed that individuals with a higher PGS lost modestly more weight during the first year. However, this group was also at higher risk of weight regain after this most intensive portion of the intervention had concluded. This may seem counterintuitive to the expectation that those with a higher genetic risk will benefit less from weight loss interventions. However, this observation is supported by a strong body of literature reporting that those most genetically predisposed to obesity are also those most responsive to changes in an obesogenic environment55–63. However, the literature on the role of genetics modifying response to weight loss interventions remains sparse and ambiguous, reflecting differences in variants considered, methods and study design, highlighting the need for well-powered PGSs64–73. It will be of interest to investigate whether PGSs for obesity have predictive utility for the fast-growing arsenal of pharmacotherapies aimed at weight loss. Separately, the current results offer crucial context when conveying genetic results of obesity risk to participants, which has generally shown either no or even short-lived adverse effects on risk-reducing behavior74–77. Rather, our findings emphasize that individuals with a high genetic predisposition to obesity may respond more to lifestyle changes and, thus, contrast with the determinist view that genetic predisposition is unmodifiable78. This is further reinforced by evidence that polygenic susceptibility can mitigate or exacerbate the impact of pathogenic variants in MC4R, underscoring the complexity of genetic influences on obesity79. We look forward to the findings of the Electronic MEdical Records and GEnomics (eMERGE) network’s PGS-based genome-informed risk assessment being returned to 25,000 diverse adults and children for 11 conditions, including obesity/BMI14. Taken together, we show that BMI PGSs can be used for prediction of adult obesity throughout the life course, particularly in early life, and for severe obesity. This PGS represents a substantial improvement compared to previous scores and may help to identify individuals at high risk to allow for timely prevention or treatment of obesity, such as through integration in a broader predictive framework jointly mod- eling genetic and environmental risk. 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The role of polygenic susceptibility to obesity among carriers of pathogenic mutations in MC4R in the UK Biobank population. PLoS Med. 17, e1003196 (2020). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. 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Kiemeney100,381, Bong-Jo Kim132, Eung Kweon Kim382,383, Hyung-Lae Kim384, Paulus Kirchhof385,386,387,388, Mika Kivimaki389,390, Woon-Puay Koh391, Nature Medicine | Volume 31 | September 2025 | 3151–3168 3162 Article https://doi.org/10.1038/s41591-025-03827-z 1The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 2Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 3Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 4Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 5MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. 6Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. 7Atlanta VA Health Care System, Decatur, GA, USA. 8Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA. 9Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. 10Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China. 11Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA. 12Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. 13Department of Public Health, Section of Epidemiology, Algorithmic Fairness Research Group, University of Copenhagen, Copenhagen, Denmark. 14Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 15Center for Genomic Data Analytics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 16Department of Internal Medicine, Division of Cardiology, Heikki A. Koistinen114,392,393, Alexander Kokkinos394, Jaspal S. Kooner299,300,395,396, Charles Kooperberg110, Peter Kovacs397, Adriaan Kraaijeveld238, Peter Kraft126, Ronald M. Krauss229, Meena Kumari398, Zoltan Kutalik38,39, Markku Laakso399, Leslie A. Lange400, Claudia Langenberg169,401,402, Lenore J. Launer216, Hyejin Lee403, Nanette R. Lee293, Terho Lehtimäki172,173, Rozenn N. Lemaitre48, Huaixing Li131, Liming Li404,405, Wolfgang Lieb406, Xu Lin131,407, Lars Lind109, Allan Linneberg140,408, Ching-Ti Liu80, Jianjun Liu85, Markus Loeffler123,124, Barry London409, Fan Lu365, Steven A. Lubitz69,323,324, David A. Mackey350,352, Patrik K. E. Magnusson410, JoAnn E. Manson45,60,74, Gregory M. Marcus411, Pedro Marques Vidal412,413, Nicholas G. Martin104, Winfried März76,414,415, Fumihiko Matsuda145, Mark I. McCarthy34,376, Robert W. McGarrah416,417, Matt McGue260, Amy Jayne McKnight65, Sarah E. Medland418, Dan Mellström192,419, Andres Metspalu35, Braxton D. Mitchell209,210,334, Paul Mitchell420, Dennis O. Mook-Kanamori2,421, Trevor A. Mori287, Andrew D. Morris422, Lorelei A. Mucci126, Patricia B. Munroe21,246, Mike A. Nalls159,160,423, Saman Nazarian424, Amanda E. Nelson44,425, Matt J. Neville376,377, Christopher Newton-Cheh215,324, Christopher S. Nielsen426,427, Harri Niinikoski189,190, Kjell Nikus174,428, Markus M. Nöthen429, Adesola Ogunniyi430, Claes Ohlsson192,431, Albertine J. Oldehinkel206, Lorena Orozco432, Katja Pahkala189,190,433, Päivi Pajukanta42,434, Colin N. A. Palmer435, Esteban J. Parra155, Cristian Pattaro99, Oluf Pedersen3, Craig E. Pennell122,208, Brenda W. J. H. Penninx183, Louis Perusse71,436, Annette Peters88,437,438, Patricia A. Peyser47, David J. Porteous63, Danielle Posthuma136, Chris Power439, Peter P. Pramstaller99, Michael A. Province243, Bruce M. Psaty48,440,441, Qibin Qi361, Jia Qu365, Daniel J. Rader52,442, Olli T. Raitakari189,190,443,444, Loukianos S. Rallidis445, Dabeeru C. Rao446, Susan Redline45,60, Dermot F. Reilly447, Alexander P. Reiner110,440, Sang Youl Rhee448, Paul M. Ridker45,74, Michiel Rienstra239, Samuli Ripatti25,49,449, Marylyn D. Ritchie52, Fernando Rivadeneira36, Dan M. Roden450, Frits R. Rosendaal2, Jerome I. Rotter108, Igor Rudan148, Femke Rutters220, Seungho Ryu150,451,452, Charumathi Sabanayagam303,453, Babatunde Salako454, Danish Saleheen205,455, Veikko Salomaa114, Nilesh J. Samani55,56, Dharambir K. Sanghera456,457,458,459, Naveed Sattar460, Börge Schmidt96, Helena Schmidt461, Reinhold Schmidt120, Matthias B. Schulze87,88,462, Heribert Schunkert463, Laura J. Scott11, Rodney J. Scott464, Peter Sever396, Wayne H. H. Sheu465, M. Benjamin Shoemaker466, Xiao-Ou Shu61, Eleanor M. Simonsick328, Mario Sims467, Andrew B. Singleton159, Moritz F. Sinner378,468, J. Gustav Smith469,470,471, Harold Snieder196, Tim D. Spector70, Beatrice Spedicati62,214, Meir J. Stampfer126,321,322, Klaus J. Stark53, David P. Strachan472, Yasuharu Tabara145, E. Shyong Tai66,473, Hua Tang474, Jean-Claude Tardif167,475, Thangavel A. Thanaraj175, Anke Tönjes397, Tiinamaija Tuomi49,171,476,477,478, Jaakko Tuomilehto114,479,480, Maria-Teresa Tusié-Luna276,481, Rob M. van Dam66,482, Pim van der Harst238,239, Nathalie Van der Velde36,483, Cornelia M. van Duijn31,78, Natasja M. van Schoor484, Veronique Vitart179, Marie-Claude Vohl436,485, Uwe Völker228,486, Peter Vollenweider412,413, Henry Völzke228,487, Scott Vrieze260, Niels H. Wacher-Rodarte488, Mark Walker489, Gurpreet S. Wander490, Nicholas J. Wareham169, Richard M. Watanabe491,492,493, Hugh Watkins34,103, David R. Weir93, Thomas M. Werge43,408, Elisabeth Widen49, Gonneke Willemsen125, Walter C. Willett126,322, James F. Wilson148,179, Peter W. F. Wilson7,494, Tien Y. Wong367,495, Jeong-Taek Woo448, Alan F. Wright179, Huichun Xu209,210, Chittaranjan S. Yajnik496, Jian Yang497,498, Mitsuhiro Yokota499, Jian-Min Yuan500,501, Eleftheria Zeggini207,502, Babette S. 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Young19, Segun Fatumo   402,516, Jeanne M. McCaffery517, Nicholas J. Timpson   5,6, Joel N. Hirschhorn29,129,518, Yan V. Sun   7,8, Sonja I. Berndt9 & Ruth J. F. Loos   1,3,4,519 Nature Medicine | Volume 31 | September 2025 | 3151–3168 3163 Article https://doi.org/10.1038/s41591-025-03827-z University of Michigan, Ann Arbor, MI, USA. 17Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 18Department of Population Health Sciences, Geisinger, Danville, PA, USA. 19Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 20Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. 21William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 22Digital Environment Research Institute, Queen Mary University of London, London, UK. 23Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 24Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan. 25Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 26Divisions of Genetics and Rheumatology, Brigham and Women’s Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA. 27Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 28Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, USA. 29Division of Endocrinology, Boston Children’s Hospital, Boston, MA, USA. 30Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA. 31Nuffield Department of Population Health, University of Oxford, Oxford, UK. 32Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK. 33Center for Health Data Science, Section for Health Data Science and Artificial Intelligence, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 34Nuffield Department of Medicine, Centre for Human Genetics, University of Oxford, Oxford, UK. 35Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia. 36Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 37Division of Biostatistics and Epidemiology, RTI International, Durham, NC, USA. 38Center for Primary Care and Public Health, University of Lausanne, Lausanne, Switzerland. 39Swiss Institute of Bioinformatics, Lausanne, Switzerland. 40Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 41Department of Family Medicine, University of California, San Diego, La Jolla, CA, USA. 42Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 43Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark. 44Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 45Harvard Medical School, Boston, MA, USA. 46Genomic Research on Complex Diseases (GRC-Group), CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India. 47Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA. 48Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA. 49Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland. 50Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 51Quantinuum Research, LLC, Wayne, PA, USA. 52Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA. 53Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany. 54Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany. 55Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. 56NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. 57Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA. 58Department of Congenital Disorders and Danish National Biobank, Statens Serum Institut, Copenhagen, Denmark. 59Department of Public Health, University of Copenhagen, Copenhagen, Denmark. 60Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA. 61Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. 62Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy. 63Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK. 64Usher Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, UK. 65Centre for Public Health, Queen’s University of Belfast, Northern Ireland, UK. 66Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore. 67Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. 68Center for Spatial and Functional Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 69Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 70Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK. 71Department of Kinesiology, Faculty of Medicine, Université Laval, Québec, QC, Canada. 72Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia. 7323andMe, Inc., Sunnyvale, CA, USA. 74Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, USA. 75Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany. 76Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 77Dipartimento di Scienze Mediche Chirurgiche e Sperimentali, Università degli Studi di Sassari, Sassari, Italy. 78Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 79Section of Statistical Multi-omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford, UK. 80Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. 81Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany. 82Department of Nutrition Science and Dietetics, School of Health Sciences, University of the Peloponnese, Kalamata, Greece. 83Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece. 84Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA. 85Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. 86Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 87Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 88German Center for Diabetes Research (DZD), Neuherberg, Germany. 89COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. 90Department of Pediatrics, Division of Endocrinology, Boston Children’s Hospital, Boston, MA, USA. 91Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK. 92Molecular Genetics Section, Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. 93Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA. 94Department of Computational Genomics, National Institute of Genomic Medicine, Mexico City, Mexico. 95Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria. 96Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany. 97Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany. 98Rogel Cancer Center, University of Michigan Medicine, Ann Arbor, MI, USA. 99Eurac Research Institute for Biomedicine, Bolzano, Italy. 100Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands. 101Jackson Heart Study, Department of Medicine, University of Mississippi, Jackson, MS, USA. 102Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. 103Cardiovascular Medicine/Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. 104Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. 105Department of Biomedicine (Human Genetics) and iSEQ Center, Aarhus University, Aarhus, Denmark. 106The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. 107BiRC - Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark. 108The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA. 109Department of Medical Sciences, Uppsala University, Uppsala, Sweden. 110Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA. 111Translational Research Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 112Danish Headache Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Nature Medicine | Volume 31 | September 2025 | 3151–3168 3164 Article https://doi.org/10.1038/s41591-025-03827-z Copenhagen, Denmark. 113Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 114Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland. 115Bristol Dental School, University of Bristol, Bristol, UK. 116Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA. 117Framingham Heart Study, Framingham, MA, USA. 118Department of Clinical Sciences in Malmö, Lund University, Lund, Sweden. 119Veterans Affairs Boston Healthcare System, Boston, MA, USA. 120Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria. 121Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria. 122School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia. 123Leipzig University, Medical Faculty, Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Germany. 124Leipzig University, Medical Faculty, LIFE Research Center for Civilization Diseases, Leipzig, Germany. 125Department of Biological Psychology, Behaviour and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. 126Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 127School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, Guangdong, China. 128Institute for Global Health and Development, Peking University, Beijing, China. 129Program in Metabolism and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 130Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. 131Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. 132Division of Genome Science, Department of Precision Medicine, National Institute of Health, Cheongwon-gun, Republic of Korea. 133Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 134Biomedical Technology Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan. 135Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. 136Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. 137Department of Child and Adolescent Psychiatry and Pediatric Psychology, Section Complex Trait Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. 138Department of Biobank Research, Umeå University, Umeå, Sweden. 139Department of Odontology, Umeå University, Umeå, Sweden. 140Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Frederiksberg, Denmark. 141Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 142Department of Nutrition and Dietetics, School of Physical Education, Sport Science and Dietetics, University of Thessaly, Trikala, Greece. 143Faculty of Medicine, University of Kelaniya, Colombo, Sri Lanka. 144Osaka University Graduate School of Medicine, Osaka, Japan. 145Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. 146Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA. 147Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA. 148Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, Scotland. 149Centre for Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh, Edinburgh, Scotland. 150Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea. 151Center for Clinical Epidemiology, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea. 152SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany. 153Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden. 154Department of Computer Science, University of Toronto, Toronto, ON, Canada. 155Department of Anthropology, University of Toronto at Mississauga, Mississauga, ON, Canada. 156Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Qld University of Technology, Kelvin Grove, Queensland, Australia. 157Oneomics, Soonchunhyang Mirai Medical Center, Gyeonggi-do, Republic of Korea. 158Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. 159Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. 160Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, USA. 161Data Tecnica International, Glen Echo, MD, USA. 162Centre for Innovation and Precision Eye Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 163Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 164Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Rockville, MD, USA. 165Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. 166Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA. 167Montreal Heart Institute, Montreal, QC, Canada. 168Departments of Ophthalmology and Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. 169MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK. 170Department of Clinical Science, Center for Diabetes Research, University of Bergen, Bergen, Norway. 171Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden. 172Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland. 173Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 174Department of Cardiology, Heart Center, Tampere University Hospital, Tampere, Finland. 175Department of Genetics & Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait. 176National and Kapodistrian University of Athens, Dromokaiteio Psychiatric Hospital, Athens, Greece. 177NIHR Biomedical Research Centre at Guy’s and St. Thomas’ Foundation Trust, London, UK. 178Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA. 179MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, Scotland. 180Department of Community Health & Epidemiology and Faculty of Computer Science, Dalhousie University, Halifax, NS, Canada. 181Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany. 182Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany. 183Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience Amsterdam UMC/Vrije Universiteit, Amsterdam, The Netherlands. 184Biomedical and Translational Informatics Institute, Geisinger, Danville, PA, USA. 185Department of Genetics, Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 186Department of Clinical Chemistry, Tampere University Hospital, Wellbeing Services County of Pirkanmaa, Tampere, Finland. 187Institute for Cardiogenetics, University of Lübeck, DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel and University Heart Center Lübeck, Lübeck, Germany. 188Institute of Epidemiology and Biobank PopGen, University Hospital Schleswig Holstein, Campus Kiel and Kiel University, Kiel, Germany. 189Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland. 190Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. 191Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan. 192Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 193Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 194Korea Institute of Science and Technology, Gangneung Institute of Natural Products, Gangneung, Republic of Korea. 195Department of Clinical Biochemistry, Lillebaelt Hospital, Kolding, Denmark. 196Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 197Department of Human Genetics, Wellcome Sanger Institute, Hinxton, UK. 198Health Campus The Hague/Public Health and Primary Care, Leiden University Medical Center, The Hague, The Netherlands. 199Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy. 200Department of Nature Medicine | Volume 31 | September 2025 | 3151–3168 3165 Article https://doi.org/10.1038/s41591-025-03827-z Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark. 201The National Centre for Register-based Research, University of Aarhus, Aarhus, Denmark. 202Medical School, University of Split, Šoltanska 2, Split, Croatia. 203Algebra University College, Zagreb, Croatia. 204Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA, USA. 205Center for Non-Communicable Diseases, Karachi, Pakistan. 206Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 207Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. 208Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia. 209Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA. 210Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA. 211Unit of Genomics of Complex Diseases, Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain. 212Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden. 213Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. 214Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy. 215Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. 216Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. 217Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea. 218Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Cagliari, Italy. 219Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. 220Department of Epidemiology and Data Science, Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences Institute, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands. 221Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA. 222Icelandic Heart Association, Kopavogur, Iceland. 223deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. 224Department of Public Health Sciences, Parkinson School of Health Sciences and Public Health, Loyola University Chicago, Maywood, IL, USA. 225VA Palo Alto Health Care System, Palo Alto, CA, USA. 226Gladstone Institute of Data Science and Biotechnology, Gladstone Institute, San Francisco, CA, USA. 227Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany. 228DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. 229Cardiology Division, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. 230Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. 231Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands. 232Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. 233Central Diagnostic Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 234Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA. 235Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 236Laboratory of Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences Institute, Amsterdam, The Netherlands. 237Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. 238Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 239Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 240Department of Biobehavioral Health, Pennsylvania State University, University Park, PA, USA. 241Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 242Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. 243Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. 244Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China. 245Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA. 246NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 247Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China. 248Information Management Services, Inc., Calverton, UK. 249Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK. 250Department of Dermatology, Medical University of Vienna, Vienna, Austria. 251Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway. 252Department of Neurology, Oslo University Hospital, Oslo, Norway. 253Unit for Lifelong Health and Ageing at UCL, Institute of Cardiovascular Science, University College London, London, UK. 254Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany. 255Department of Medicine IV – Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany. 256Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA. 257Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, Japan. 258Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA. 259Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. 260Department of Psychology, University of Minnesota, Minneapolis, MN, USA. 261Department of Genetic Medicine, Weill Cornell Medicine, Doha, Qatar. 262Department of Computer and Systems Engineering, Alexandria University, Alexandria, Egypt. 263Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany. 264Department of Epidemiology and Biostatistics, Imperial College London, London, UK. 265Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. 266Victor Phillip Dahdaleh Heart & Lung Research Institute, Cambridge Biomedical Campus, Cambridge, UK. 267Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. 268Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. 269Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 270Amsterdam Cardiovascular Sciences Institute, Amsterdam, The Netherlands. 271Molecular Epidemiology Section, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands. 272Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 273Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 274Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. 275Latin American Brain Health (BrainLat), Universidad Adolfo Ibáñez, Santiago, Chile. 276Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. 277Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico. 278Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA. 279Department of Cardiology, Amsterdam Cardiovascular Sciences Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 280Institute of Health Informatics, University College London, London, UK. 281The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, UK. 282HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, NTNU, Trondheim, Norway. 283HUNT Research Center, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger, Norway. 284Department of Endocrinology, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. 285Department of Nephrology, University Hospital Regensburg, Regensburg, Germany. 286Geriatric Unit, Azienda Toscana Centro, Florence, Italy. 287Medical School, Royal Perth Hospital Unit, University of Western Australia, Perth, Western Australia, Australia. 288Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru Nature Medicine | Volume 31 | September 2025 | 3151–3168 3166 Article https://doi.org/10.1038/s41591-025-03827-z University (JNU), New Delhi, India. 289Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy. 290Human Genetics Center and Department of Epidemiology, The University of Texas Health Science Center at Houston, Houston, TX, USA. 291Department of Nephrology and Rheumatology, Kliniken Südostbayern, Regensburg, Germany. 292KfH Kidney Center Traunstein, Traunstein, Germany. 293USC-Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City, Philippines. 294Department of Nutrition and Dietetics, University of San Carlos, Cebu City, Philippines. 295Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA. 296Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark. 297Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. 298Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. 299Department of Cardiology, Ealing Hospital, London North West University Healthcare NHS Trust, Middlesex, UK. 300Imperial College Healthcare NHS Trust, Imperial College London, London, UK. 301Lightening Lives, Hyderabad, India. 302Department of Ophthalmology, National University of Singapore and National University Health System, Singapore, Singapore. 303Ocular Epidemiology, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore. 304Danish Aging Research Center, University of Southern Denmark, Odense, Denmark. 305Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. 306Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway. 307IRCCS Neuromed, Pozzilli (IS), Pozzilli, Italy. 308Department of Neurology, Division of Vascular Neurology, University of Maryland School of Medicine, Baltimore, MD, USA. 309Department of Neurology, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA. 310Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico. 311Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy. 312Intermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA. 313Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA. 314Department of Vascular Surgery, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands. 315Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC/Vrije Universiteit, Amsterdam, The Netherlands. 316Department of Human Nutrition, Wageningen University, Wageningen, The Netherlands. 317Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA. 318Department of Oncology, University of Cambridge, Cambridge, UK. 319Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Berlin, Germany. 320Department of General Practice, Amsterdam Public Health Institute, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands. 321Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA. 322Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 323Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA. 324Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. 325Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia. 326Department of Cardiology, St. Vincent’s Hospital, Darlinghurst, New South Wales, Australia. 327Faculty of Medicine, UNSW Sydney, Kensington, New South Wales, Australia. 328Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. 329Department of Medicine, Harvard Medical School, Boston, MA, USA. 330Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA. 331Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK. 332Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA. 333Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Helsingborg, Sweden. 334Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA. 335Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA. 336Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health, Neuherberg, Germany. 337College of Allied Health Professions, University of Nebraksa Medical Center, Omaha, NE, USA. 338Centro de Investigacion en Salud Poblacional Instituto Nacional de Salud Publica and Centro de Estudios en Diabetes, Cuernavaca Morelos, Mexico. 339Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 340Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 341Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 342Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 343Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. 344Division of Pulmonary Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 345Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK. 346Khoo Teck Puat - National University Children’s Medical Institute, National University Health System, Singapore, Singapore. 347Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria. 348Research Unit of Biomedicine and Internal Medicine, Biocenter of Oulu, Medical Research Center, University of Oulu, Oulu, Finland. 349Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznań, Poland. 350Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. 351Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia. 352Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia, Australia. 353Division of Cardiology, Massachusetts General Hospital, Boston, MA, USA. 354Department of Genetics, Shanghai-MOST Key Laboratory of Heath and Disease Genomics, Chinese National Human Genome Center and Shanghai Industrial Technology Institute, Shanghai, China. 355Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA. 356Department of Pediatrics, Tampere University Hospital, Tampere, Finland. 357Department of Pediatrics, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 358Australian Centre for Precision Health, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia. 359South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia. 360Department of Environmental and Preventive Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan. 361Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA. 362Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulun, Finland. 363Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland. 364Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK. 365The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, China. 366Institut Français de Myopie, Hôpital Fondation Rothschild, Paris, France. 367Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore. 368Privatpraxis Prof. Jonas und Dr. Panda-Jonas, Heidelberg, Germany. 369L V Prasad Eye Institute, Hyderabad, India. 370Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands. 371Netherlands Heart Institute, Utrecht, The Netherlands. 372Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland. 373Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 374Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. 375Department of Ophthalmology, The Catholic University of Korea Incheon St. Mary’s Hospital, Incheon, Republic of Korea. 376Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK. 377NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK. 378German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany. 379Verve Therapeutics, Boston, MA, USA. 380Brigham and Women’s Hospital, Boston, MA, USA. 381Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands. 382Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. 383Saevit Eye Hospital, Goyang-si, Republic of Korea. 384Department of Biochemistry, College of Medicine, Nature Medicine | Volume 31 | September 2025 | 3151–3168 3167 Article https://doi.org/10.1038/s41591-025-03827-z Ewha Womans University, Seoul, Republic of Korea. 385Department of Cardiology, University Heart and Vascular Center UKE Hamburg, Hamburg, Germany. 386Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. 387German Center for Cardiovascular Research, Partner Site, Hamburg/Kiel/Lübeck, Germany. 388Atrial Fibrillation NETwork, Münster, Germany. 389UCL Brain Sciences, University College London, London, UK. 390Clinicum, University of Helsinki, Helsinki, Finland. 391Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 392Department of Medicine, University of Helsinki, Helsinki University Hospital, Helsinki, Finland. 393Minerva Foundation Institute for Medical Research, Helsinki, Finland. 394First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece. 395MRC-PHE Centre for Environment and Health, Imperial College London, London, UK. 396National Heart and Lung Institute, Imperial College London, London, UK. 397Medical Department III – Endocrinology, Nephrology, Rheumatology, Leipzig University Medical Center, Leipzig, Germany. 398Institute for Social and Economic Research, University of Essex, Wivenhoe Park, UK. 399Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. 400Department of Medicine, University of Colorado at Denver, Aurora, CO, USA. 401Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany. 402Precision Healthcare University Research Institute, Queen Mary University of London, London, UK. 403Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Republic of Korea. 404Department of Epidemiology and Biostatistics, Peking University Health Science Center, Beijing, China. 405Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China. 406Institute of Epidemiology and Biobank Popgen, Kiel University, Kiel, Germany. 407Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, China. 408Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 409Division of Cardiovascular Medicine and Abboud Cardiovascular Research Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. 410Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 411Division of Cardiology, University of California, San Francisco, San Francisco, CA, USA. 412Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland. 413University of Lausanne, Lausanne, Switzerland. 414SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany. 415Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. 416Department of Medicine, Division of Cardiology, Duke University School of Medicine, Durham, NC, USA. 417Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA. 418Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. 419Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 420Centre for Vision Research and Department of Ophthalmology, Westmead Millennium Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia. 421Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands. 422Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK. 423Data Tecnica, Washington, DC, USA. 424Electrophysiology Section, Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 425Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 426Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway. 427Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway. 428Department of Cardiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology Tampere University, Tampere, Finland. 429Institute of Human Genetics, School of Medicine & University Hospital Bonn, Bonn, Germany. 430Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria. 431Department of Drug Treatment, Sahlgrenska University Hospital, Gothenburg, Sweden. 432Laboratorio de Inmunogenómica y Enfermedades Metabólicas, Instituto Nacional de Medicina Genómica, CDMX, Mexico City, Mexico. 433Paavo Nurmi Centre and Unit for Health and Physical Activity, University of Turku, Turku, Finland. 434Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 435Pat MacPherson Centre for Pharmacogenetics and Pharmacogenomics, Division of Population Health and Genomics, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK. 436Centre Nutrition, santé et société (NUTRISS), Institute of Nutrition and Functional Foods, Université Laval, Québec, QC, Canada. 437Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. 438Institute for Medical Information Processing, Biometry and Epidemiology, Medical Faculty, Ludwig Maximilians Universität München, Munich, Germany. 439Population, Policy and Practice, UCL Great Ormond Street Hospital Institute of Child Health, London, UK. 440Department of Epidemiology, University of Washington, Seattle, WA, USA. 441Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA. 442Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 443Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland. 444InFLAMES Research Flagship, University of Turku, Turku, Finland. 445Second Department of Cardiology, Medical School, National and Kapodistrian University of Athens, University General Hospital Attikon, Athens, Greece. 446Center for Biostatistics and Data Science, Washington University School of Medicine, St. Louis, MO, USA. 447Genetics, Merck Sharp & Dohme Corp., Kenilworth, NJ, USA. 448Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Dongdaemun-gu, Seoul, Republic of Korea. 449Department of Public Health, Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland. 450Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA. 451Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 452Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 453Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore. 454Department of Medicine, University of Ibadan, Ibadan, Nigeria. 455Department of Cardiology and Department of Medicine, Columbia University, Columbia, NY, USA. 456Department of Pediatrics, Section of Genetics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 457Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 458Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 459Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. 460Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK. 461Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Graz, Austria. 462Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany. 463Deutsches Herzzentrum München, Cardiology, Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK) – Munich Heart Alliance and Technische Universität München, München, Germany. 464School of Biomedical Science and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia. 465Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan. 466Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. 467Department of Social Medicine, Population and Public Health, School of Medicine, University of California, Riverside, Riverside, CA, USA. 468Department of Medicine I, University Hospital, LMU Munich, Munich, Germany. 469Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden. 470The Wallenberg Laboratory/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University and the Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden. 471Wallenberg Center for Molecular Medicine and Lund University Diabetes Center, Lund University, Lund, Sweden. 472Population Health Research Institute, St. George’s University of London, London, UK. 473Yong Loo Lin School of Nature Medicine | Volume 31 | September 2025 | 3151–3168 3168 Article https://doi.org/10.1038/s41591-025-03827-z Medicine, National University of Singapore and National University Health System, Singapore, Singapore. 474Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. 475Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada. 476Helsinki University Hospital, Helsinki, Finland. 477Helsinki University Central Hospital, Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland. 478Folkhälsan Research Center, Helsinki, Finland. 479Department of Public Health, University of Helsinki, Helsinki, Finland. 480Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia. 481Unidad de Biología Molecular y Medicina Genómica, Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico. 482Milken Institute School of Public Health, The George Washington University, Washington, DC, USA. 483Department of Geriatric Medicine, Amsterdam Public Health, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands. 484Department of Epidemiology and Data Science, Amsterdam UMC, Amsterdam, The Netherlands. 485School of Nutrition, Faculty of Agricultural and Food Sciences, Université Laval, Québec, QC, Canada. 486Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany. 487Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. 488Unidad de Investigación Médica en Epidemiología Clínica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico. 489Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. 490Hero DMC Heart Institute, Dayanand Medical College, Ludhiana, India. 491Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA. 492Department of Physiology & Neuroscience, Keck School of Medicine of USC, Los Angeles, CA, USA. 493USC Diabetes and Obesity Research Institute, Keck School of Medicine of USC, Los Angeles, CA, USA. 494Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA. 495School of Clinical Medicine, Beijing Tsinghua Changgung Hospital, Tsinghua Medicine, Tsinghua University, Beijing, China. 496Diabetes Unit, KEM Hospital and Research Centre, Pune, India. 497School of Life Sciences, Westlake University, Hangzhou, China. 498Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. 499Kurume University School of Medicine, Kurume, Japan. 500Cancer Epidemiology and Prevention Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. 501Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. 502Technical University of Munich and Klinikum Rechts der Isar, TUM School of Medicine and Health, Munich, Germany. 503Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. 504The Institute of Cancer Research, London, UK. 505Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. 506Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA. 507Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA. 508Department of Medicine, Veterans Affairs Boston Healthcare System, Boston, MA, USA. 509Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia. 510Department of Genetic Medicine and Development, Centre Medical Universitaire, University of Geneva, Geneva, Switzerland. 511McDonnell Genome Institute and Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. 512Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 513Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 514Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka, Japan. 515Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA. 516MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda. 517Department of Allied Health Sciences, University of Connecticut, Storrs, CT, USA. 518Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA, USA. 519The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 520Present address: Department of Mathematics and Statistics, St. Cloud State University, St. Cloud, MN, USA. 520Deceased: Richard S. Cooper. 521Deceased: Jeanette Erdmann. 522Deceased: David M. Hougaard. *Lists of authors and their affiliations appear at the end of the paper.  e-mail: ruth.loos@sund.ku.dk 23andMe Research Team Adam Auton73, Yunxuan Jiang73 & Jingchunzi Shi73 Full lists of members and their affiliations appear in the Supplementary Information. DiscovEHR (DiscovEHR and MyCode Community Health Initiative) Geetha Chittoor18, Anne E. Justice18,19, Jason E. Miller184,185 & Shefali S. Verma67 eMERGE (Electronic Medical Records and Genomics Network) Yuki Bradford52, Marylyn D. Ritchie52, Yogasudha Veturi240 & Xinyuan Zhang52 GPC-UGR Segun Fatumo402,516 & Mariam Nakabuye13 The PRACTICAL Consortium Sonja I. Berndt9 Understanding Society Scientific Group Meena Kumari398, Lorraine Southam207 & Eleftheria Zeggini207,502 VA Million Veteran Program Themistocles L. Assimes225,505, Yuk-Lam Ho119, Jie Huang127,128, Jennifer E. Huffman119, Qin Hui7,8, Christopher J. O’Donnell45,60,508, Saiju Pyarajan45,60,204, Yan V. Sun7,8, Catherine Tcheandjieu225,226 & Peter W. F. Wilson7,494 Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z Methods Study populations The list of studies contributing to the GWAS meta-analyses for BMI, which served as the training data for the presented PGSs, is provided in Supplementary Table 1. The study populations described below are those that contributed as a PGS tuning or validation population. The UKBB is a prospective cohort study that enrolled approx- imately 500,000 people from across the UK, aged 40–69 years at recruitment, between 2006 and 2010 (ref. 18). At recruitment, par- ticipants completed detailed questionnaires, underwent a range of physical measures and provided blood, urine and saliva samples. BMI was calculated using height (measured in whole centimeters) and weight (to the nearest 0.1 kg). Females who were pregnant at the time of assessment were excluded from our analysis. As a measure of com- parative childhood body size, participants were asked: ‘When you were 10 years old, compared to average, would you describe yourself as: (i) thinner, (ii) plumper, (iii) about average?’. The MVP has recruited over 1 million people from Veteran Affairs (VA) Medical Centers across the United States since 2011 (ref. 19). Veterans who volunteer provide a blood sample for biobanking, com- plete baseline and lifestyle questionnaires and consent to allow access to clinical data from VA electronic health records (EHRs). For the cur- rent study, PGS performance was assessed in the MVP’s third release of genomic data (R3) using additional participants without overlap, with earlier data releases contributing to the GIANT GWAS meta-analyses. Phenotypic and genomic data related to the association analysis of BMI were previously described20. The Institute for Personalized Medicine BioMe Biobank, founded in 2007, is an ancestrally and culturally highly diverse EHR-linked biore- pository enrolling participants non-selectively from across the Mount Sinai Health System in New York City21. At enrollment, participants consent to link their DNA and plasma samples to deidentified EHRs. The clinical and EHR information is complemented by a baseline ques- tionnaire that gathers demographic and lifestyle information. BMI was calculated using weight and height from baseline and outpatient EHR measurements, using median height and weight measured at or within 60 days before/after the enrollment visit, after several cleaning steps (Supplementary Table 3). The GPC-UGR is a population-based open cohort study estab- lished in 1989 by the Medical Research Council (UK) in collaboration with the Uganda Virus Research Institute (UVRI) to monitor the HIV epidemic and its determinants in neighboring villages in rural south- western Uganda, in the Kyamulibwa subcounty of the Kalungu district, approximately 120 km from Entebbe town. Since 2010, its mandate has expanded to incorporate the epidemiology and genetics of both communicable and non-communicable diseases22. The GPC-UGR was initially recruited and assessed through annual house-to-house census and survey rounds until 2012, when biannual surveys commenced. For the current study, we included individuals aged 18 years and older who have been either whole-genome genotyped or whole-genome sequenced80,81. The ALSPAC is a prospective birth cohort from the southwest of England established to investigate environmental and genetic char- acteristics that influence health, development and growth of children and their parents27–29. Full details of the cohort and study design are available at http://www.alspac.bris.ac.uk. In brief, pregnant females residing in Avon, UK, with expected dates of delivery between 1 April 1991 and 31 December 1992 were invited to take part in the study. The initial number of pregnancies enrolled was 14,541, with 13,988 children who were alive at 1 year of age. The children resulting from these preg- nancies have been followed-up to date with measures obtained through regular questionnaires and clinical visits, providing information on a range of behavioral, lifestyle and biological data. More specifically, a 10% sample of the ALSPAC cohort, known as the Children in Focus (CiF) group, attended clinics at the University of Bristol at various time intervals between 4 months and 61 months of age, whereas the entire ALSPAC cohort was invited to attend regular research clinics from age 7. When the oldest children were approximately age 7, an attempt was made to bolster the initial sample with eligible individuals who had failed to join the study originally. The total sample size available for analyses using any data collected after the age of 7 is, therefore, 15,447 pregnancies, with 14,901 children who were alive at 1 year of age. Study data were collected and managed using Research Electronic Data Capture (REDCap) tools hosted at the University of Bristol82. REDCap is a secure, web-based software platform designed to support data capture for research studies. Details on sample selection for the current analyses are presented in Supplementary Table 3. Please note that the study website contains details of all data that are available through a fully searchable data dictionary and variable search tool (http://www. bristol.ac.uk/alspac/researchers/our-data/). The PLCO Cancer Screening Trial was a multicenter randomized controlled trial in the United States that enrolled males and females aged 55–74 years from 1993 to 2001 to evaluate the effectiveness of different screening programs on cancer mortality32. In the baseline questionnaire, participants self-reported their weight at age 20 years, age 50 years and baseline as well as their height. For the current study, we restricted the analyses to genotyped participants who had not con- tributed to the underlying GWAS meta-analyses and had information available on their weight and BMI at both age 20 and age 50. The DPP was a 27-site parallel-arm randomized controlled trial designed to determine whether either the oral diabetes drug met- formin or an ILI (primarily fat gram, calorie and physical activity goals) aimed at approximately 7% weight loss, compared to inactive tablets and standard lifestyle recommendations, could prevent or delay type 2 diabetes onset in ethnically diverse high-risk individuals with predia- betes and overweight or obesity33. For the current study, we excluded individuals from the metformin arm as well as those from a fourth intervention arm, troglitazone, which was discontinued at an early stage. Moreover, we focused on the individuals comprising the three largest race and ethnicity categories (White, Black and Hispanic, as reported by database of Genotypes and Phenotypes (dbGAP) variable phv00201855.v2.p1) who had consented to being genotyped. Look AHEAD was a 16-site parallel-arm randomized controlled trial that assessed the long-term effects of an ILI in ethnically diverse patients with overweight or obesity and type 2 diabetes on cardiovas- cular morbidity and mortality37. The lifestyle intervention was modeled after the DPP lifestyle intervention and similarly aimed at 7% weight loss but with more ambitious individual goals for several intervention components83. Although those in both trial arms were provided one session of education on diabetes and cardiovascular risk at baseline, the comparison arm thereafter received the option of attending only three sessions per year on nutrition, physical activity and social sup- port, with no explicit weight loss goals. As for the DPP, we restricted our analyses to genotyped participants who self-reported as being of African American/Black, Hispanic and White race and ethnicity on the baseline questionnaire. Population descriptors and study-provided population labels and genotyping, phenotyping and participant characteristics are presented in Supplementary Tables 3 and 4. No new data (that is, measurements) were collected for this study, and no participant compensation was provided for the analyses conducted. Our research complies with all relevant ethical regulations. The UKBB study was approved by the North West Multi-Centre Research Ethics Committee (ref. 11/NW/0382), and all participants provided written informed consent to participate in the UKBB study. The VA central institutional review board (IRB) approved the MVP study pro- tocol in accordance with the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all participants. The BioMe Biobank Program (IRB no. 07-0529) operates under a Mount Sinai IRB-approved research protocol. All study participants Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z provided written informed consent. The Uganda Genome Resource was approved by the Science and Ethics Committee of the UVRI Research and Ethics Committee (UVRI-REC no. HS 1978), the Uganda National Council for Science and Technology (UNCST no. SS 4283) and the East of England-Cambridge South (formerly Cambridgeshire 4) NHS Research Ethics Committee UK. Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the local research ethics committees. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). 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. The PLCO study was approved by the human subjects review boards at the National Cancer Institute and at the 10 study centers (National Institutes of Health IRB no. OH97CN041). Written informed consent was given by all participants. The DPP and Look AHEAD trials were approved by the IRB at each center, and all participants gave written informed consent. PGS construction and tuning To derive our scores, we used summary statistics from the ongoing GWAS meta-analyses for BMI conducted by the GIANT consortium (https://portals.broadinstitute.org/collaboration/giant/index.php/ GIANT_consortium) in collaboration with 23andMe. Prior to each GWAS, BMI (kg m−2) underwent rank-based inverse-normal transfor- mation by sex, similarity to major ancestry group (AFR, AMR, EAS, EUR, SAS) and case–control status as appropriate, with age, age2, principal components of population structure and study-specific covariates regressed out. Ancestry group assignment was defined independently by each contributing study, as previously described84. Additive GWAS analyses were performed primarily using RVTESTS for 1000 Genomes Project (1000G) phase 3 or Haplotype Reference Consortium (HRC)-imputed data85. For 23andMe, which performed its GWAS on BMI using self-reported height and weight, see Supplemen- tary Table 2 for details on phenotyping, ancestry group assignment and GWAS methodology. Quality control of the study-specific files was conducted using EasyQC86, followed by fixed-effect meta-analysis by ancestry group using RAREMETAL87. When performing the GWAS meta-analyses to train the PGSs with, we purposely excluded data from several populations (ALSPAC, BioMe and UKBB). No additional genomic control was applied to the resulting summary statistics. For PGS derivation, we employed PRS-CS and its multi-ancestral extension PRS-CSx (versions 1.0.0)16,17. In short, PRS-CS(x) uses a Bayes- ian regression framework and assumes a continuous shrinkage prior on single-nucleotide polymorphism (SNP) effects. Whereas PRS-CS focuses on creating ancestry-specific scores, informed only by the GWAS summary statistics and LD information of a given population, PRS-CSx uses a shared prior to couple SNP effects across populations and explicitly models population-specific allele frequencies and LD patterns to create multi-ancestry scores. Both methods were imple- mented using the software’s default settings (that is, gamma–gamma priors set to a = 1 and b = 0.5, Markov chain Monte Carlo (MCMC) total and burn-in iterations set at 1,000 times and 500 times the num- ber of discovery populations and MC thinning factor set at 5), with input being ancestry-matched summary statistics and PRS-CS(x) developer-provided 1000G LD reference panels of common HapMap3 variants (AFR, AMR, EAS, EUR, SAS). PRS-CS(x) uses a global scaling parameter (Φ), which requires tuning. In addition to small-scale grid testing of Φ (1 × 10−6, 1 × 10−4, 1 × 10−2, 1), we ran PRS-CS(x) using its ‘auto’ option, which learns Φ automatically from the GWAS summary statistics. Finally, PRS-CSx was performed separately using its default ‘linear combination’ as well as its ‘meta’ version. In the first, a set of population-specific PGSs is outputted (that is, five in our case), for which the optimal linear combination needs to be derived for each target population (for example, AFR) in a population-matched tun- ing dataset. For ‘meta’, the population-specific posterior SNP effects are integrated using an inverse-variance weighted meta-analysis in the Gibbs sampler, producing a single score that can theoretically be applied regardless of the target population. The variants considered for PGS derivation were those present in the 1000G reference panels mentioned above (HapMap3 variants (n = 1–1.2 million across panels), which were common in 1000G popula- tions, excluding ambiguous A/T or G/C variants), which additionally had an INFO > 0.3 (that is, imputation quality) in the overall UKBB. Ancestry-specific summary statistics were further restricted to the variants with a variant-specific sample size of at least a third of the maximum sample size for that ancestry. Tuning of Φ and derivation of PRS-CSx’s linear combination weights were performed in the same subsets of the UKBB. More spe- cifically, we used genetically determined relatedness and ancestry assignments provided by the Pan-UKBB Team (https://pan.ukbb.broa- dinstitute.org, UKBB return 2442) to subset the UKBB into groups of unrelated individuals of African-like, Admixed American-like, Central/South Asian-like, East Asian-like, European-like (random subset of 20,000 individuals) and Middle Eastern-like ancestry. The target-population-specific (for example, AFR) linear combination weights for PRS-CSx (for each Φ) were derived from a joint linear regres- sion model of rank-based inverse-normal transformed BMI (by sex and population) on the five population-specific scores (each standardized to mean zero and unit variance in the corresponding tuning dataset—for example, UKBBAFR), age, 10 principal components and genotyping array. Explained variance for BMI was defined as the incremental adjusted R2 from linear regression for rank-based inverse-normal trans- formed BMI (by sex and population), when adding the PGS predictor to a model containing age, principal components and genotyping array. Confidence intervals (95%) were determined using bootstrap- ping with 1,000 repetitions. As comparator, we created a score of quasi-independent associations after performing approximate con- ditional and joint (COJO) multiple-SNP analysis88, as implemented in GCTA89, using the results from the multi-ancestral GWAS summary sta- tistics when leaving out only the UKBB. We used genotypes from a previ- ously described set of 50,000 unrelated UKBBEUR participants 84 as our LD reference panel for GCTA-COJO, with parameters set to: –diff-freq 0.1; –maf 0.01; –cojo-collinear 0.9; –cojo-p 5 × 10−9. The scores with the highest explained variance across multiple tuning population datasets (PRS-CSx linear combination and meta versions, with Φ 1 × 10−2) were then taken forward to the validation populations, which performed study-level variant filtering on imputation quality when constructing each PGS (Supplementary Table 3). The results of PGSmeta are presented throughout the supplementary tables. Of note, in August 2023, a new version of PRS-CSx was released (version 1.1.0) to address potential reductions in performance due to truncating of GWAS summary statistics P values below 1 × 10−323. Given our inclusion of several variants with P values below this threshold (among the PGS variants: n = 154 for EUR, n = 12 for AMR), we reran PRS-CSx with Φ 1 × 10−2 but did not observe markedly different results in PGS performance within the UKBB tuning populations (Supplemen- tary Table 18). PGS performance in adulthood In addition to explained variance (%) for BMI, several population- stratified metrics for overall performance and discrimination were calculated in the validation studies with adult participants: A. Nagelkerke R2, with a null model of age, sex, principal com- ponents and genotyping array, for prevalent obesity catego- ries based on World Health Organization (WHO) BMI cutoff points (membership of category or above versus rest), using Asian-specific cutoffs where applicable (Supplementary Table 3)23. Confidence intervals (95%) were calculated using bootstrapping with 1,000 repetitions. Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z B. Mean difference in BMI, both untransformed and after rank- based inverse-normal transformation by sex, per s.d. increase in PGS. Covariates included age, sex (where applicable), principal components and genotyping array. C. Odds ratio per s.d. of PGS for prevalent WHO obesity outcome. Same covariates as under (B). Here, the PGSs were standardized to mean zero and unit variance using the mean and s.d. of the PGS observed within participants without the outcome (for example, individuals who do not fall within obesity class I (or higher), where this was the outcome), to account for prevalence differences across studies. D. AUC statistic for prevalent WHO obesity outcomes. We com- pare models including (i) age and sex, (ii) genotyping array, principal components and PGSKhera, (iii) genotyping array, principal components and PGSLC and (iv) models (i)/(iii) com- bined. In the UKBB, we additionally ran models including and excluding self-reported comparative body size at age 10 (UKBB field ID 1687). Confidence intervals (95%) were calculated using DeLong’s method. In addition, the explained variance for BMI was calculated sepa- rately in age strata (≤50 years or >50 years, with adjustment for residual age differences within age strata) and sex strata of the European UKBB participants. The main comparator for all analyses was a previously published LDpred-derived PGS for BMI (PGSKhera) 12, which was based on the results from a GIANT consortium GWAS meta-analysis including up to 339,224 individuals of primarily European ancestry24. As BioMe had contributed to this meta-analysis, metrics for PGSKhera were determined in individuals who had not contributed nor were related to those who did (second or stronger degree of relatedness, based on KING-derived kinship coefficients). We chose PGSKhera as our comparator as it is the most widely recognized and extensively used PGS for BMI within the obesity research community, thereby serving as a well-established benchmark. Tail comparisons after ancestry correction Due to on-average differences in LD structure and allele frequencies, the distribution of a PGS (for example, mean and variance) can dif- fer across ancestral populations. This was also observed for the five population-specific PGSs that were linearly combined to create PGSLC (Extended Data Fig. 4). As performance metrics that rely on thresh- olding the PGS distribution (for example, top 10%) may be impacted by such on-average differences90, particularly in admixed popula- tions, we modeled the mean and variance of the population-specific PGSs through principal component analysis of the 1000G reference panel. For this, we applied a correction described by the eMERGE network14,91, which represents a modified version of the approach by Khera et al.92. Starting with a publicly available, curated version of the 1000G reference panel (https://broadinstitute.github.io/warp/ docs/Pipelines/Imputation_Pipeline/references_overview; gs:// broad-gotc-test-storage/imputation/1000 G_reference_panel), we first excluded variants with MAF < 1% across 1000G superpopulations, before determining the overlap with genotyped variants available for both the UKBB and BioMe. After excluding long-range LD regions, we pruned the list of variants using plink (–indep-pairwise 1000 50 0.05) and ran principal component analysis with flashpca93, whereafter we projected UKBB and BioMe participants to the same 1000G principal component space. For each of the five population-specific PGSs under- lying PGSLC (that is, AFR, AMR, EAS, EUR and SAS), we regressed the PGS of 1000G participants against the first 10 principal components of ancestry: PGS = α0 + 10 ∑ i=1 αi × PCi In addition, we modeled its residual variance (δ2) as a function of the same principal components: δ2 = β0 + 10 ∑ i=1 βi × PCi Then, using the projected principal component, predicted mean and residual s.d. were calculated and used to create ancestry-adjusted z-scores of each PGS for UKBB and BioMe participants: adjusted zPGS = ∑Mj=1 wj × dosagej − (α0 + ∑ 10 i=1 αi × PCi) √β0 + ∑10i=1 βi × PCi with ∑Mj=1wj × dosagej representing the raw PGS. We observed that mean and variance differences of scores across ancestry populations were largely, but not fully, resolved through this correction in both study populations (Extended Data Fig. 4). In keeping with PRS-CSx’s linear combination approach, weights to linearly combine scores were derived within each UKBB tuning population and applied to BioMe validation populations. The ancestry-adjusted PGSLC was then thresholded at its top 5% and 10% separately (versus bottom 95% and 90%, respectively), and odds ratios for prevalent obesity were calculated, adjusting for age, sex and genotyping array. Given the relatively lower number of East Asian and South Asian individuals available for these tail comparisons, we present pooled estimates. Multi-ancestry PGS trained only with GIANT consortium data Although we primarily report on the development and performance of the PGSLC trained with the larger GIANT+23andMe BMI GWAS meta-analyses results, we initially developed a multi-ancestry PGS with the GIANT-only results. For this, we used PRS-CS, combining GIANT’s combined multi-ancestral GWAS summary statistics (includ- ing BioMe but excluding the UKBB and the ALSPAC study) with a pre- viously described multi-ancestry 1000G-based LD reference panel created following the same protocol as described by the PRS-CS authors94. We restricted variants to those present in the LD reference panel, which additionally had MAF ≥ 0.1% and INFO ≥ 0.8 in the overall UKBB, resulting in a total of 1,217,710 variants included. We did not specify a genome-wide shrinkage parameter for PRS-CS, which it there- fore learned from the training data using a fully Bayesian approach (its ‘auto’ option). In collaboration with the eMERGE network, this GIANT-only PGS was included among a select group of trait-specific scores currently being returned as part of a genome-informed risk assessment (GIRA) to 25,000 diverse adults and children and their healthcare providers in an ongoing prospective cohort study across 10 clinical sites, as recently described14,48. In line with the aim of return- ing a high-risk versus a not-high-risk GIRA status to participants, we estimated the odds ratio for obesity class I (or higher) for being in the top 3% of the PGS distribution (versus bottom 97%) within the subset of BioMe participants genotyped with the Global Screening Array (with 1000G imputation) who had not contributed to the underly- ing GIANT GWAS meta-analysis nor were related to those who did. Accounting for age, sex and four principal components, we observed that values within the top 3% of this PGS were associated with 4.08 (95% confidence interval: 3.02–5.52) times as high odds for prevalent obesity in individuals of self-reported European descent, with 2.54 (95% confidence interval: 1.55–3.98) for individuals of self-reported African descent, with 2.33 (95% confidence interval: 1.64–3.31) for individuals of self-reported Hispanic/Latino descent and with 5.73 (95% confidence interval: 2.28–14.57) for individuals of self-reported Asian descent. The weights for this GIANT-only PGS are made available through the PGS Catalog alongside the weights for PGSLC and PGSmeta (see ‘Data availability’). Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z Childhood and adolescence Within the ALSPAC study, repeated anthropometric measurements are available from birth to age 24. We employed both cross-sectional and multilevel analyses to provide complementary perspectives: cross-sectional analyses facilitate granular comparisons at each timepoint, whereas multilevel models capture longitudinal trajec- tories and population-level divergence over time. First, we assessed repeated cross-sectional associations between the standardized PGS (PGSLC using linear combination weights from UKBBEUR) and all available measures of BMI (or ponderal index at birth) and height. Anthropometric measurements were rank-based inverse-normal trans- formed separately by sex, at each timepoint, and analyses were adjusted for age at timepoint and principal components. Longitudinal analyses using linear spline multilevel models were conducted to examine the association between the PGS (bottom 10%, middle 80%, top 10%) and change in untransformed BMI and height between 4 months and 24 years. Multilevel models estimate the mean trajectories of each anthropometric trait while accounting for non-independence of repeated measures within individuals, change in scale and variance of measures over time and differences in the number and timing of measurements between individuals (using all available data from all eligible participants under a missing-at-random assump- tion). Linear splines allow knot points to be fitted at different ages to derive periods of change that are approximately linear. All participants with at least one measure of the anthropometric traits were included under a missing-at-random assumption to minimize selection bias in trajectories estimated using linear spline multilevel models (with two levels of random effects: measurement occasion (that is, age to the nearest integer in years) and individual), allowing individuals to have different intercepts and slopes and, thus, their own trajectories. Knot points were placed as follows for each anthropometric trait based on the distribution and longitudinal pattern of measures between the earli- est measure and 24 years: at ages 4 months and 8 months and at ages 2.5 years, 5 years, 8 years and 15 years for BMI and at ages 1 year, 5 years and 15 years for height. Interaction terms between PGS and each spline were included in the models to estimate the difference in the intercepts (earliest anthropometric trait measurement) and slopes (change in anthropometric trait from the earliest measure to 24 years) between the three PGS categories. Additionally, interaction terms between sex and the first 10 genetic principal components with each spline were included to estimate the difference in intercepts and slopes between males and females; therefore, models were adjusted for sex and princi- pal components. All longitudinal models were created in MLwiN version 3.04 called from Stata version 15 using the ‘runmlwin’ command95. In the CiF subset of the cohort, age at adiposity rebound was avail- able, categorized as very early (at/before 43 months), early (from 49 months but before 61 months) and later (after 61 months)96. These children represent a 10% sample of the cohort, randomly selected for more detailed investigations, and are representative of the entire cohort (https://www.bristol.ac.uk/alspac/researchers/cohort-profile/). One-way ANOVA was used to test for differences in mean PGS across categories, in boys and girls separately and combined. Added value of the PGS for prediction of BMI (rank-based inverse- normal transformed by sex) at given timepoints was quantified as incremental explained variance, when adding the PGS to different sets of predictors. First, we examined R2 for BMI at birth and at 3, 5, 8, 11 and 15 years, when adding the PGS to a model containing multiple relatively easily obtainable clinical variables that would be available at birth (birthweight, maternal education, pre-pregnancy maternal BMI, maternal age at date of birth and household social status). Details regarding phenotyping of these variables can be found in Supplemen- tary Table 3. Separately, for R2 for BMI at age 18, we added the PGS to separate models containing BMI from a given early-life timepoint (1, 2, 3, 4, 5 and 8 years). Confidence intervals (95%) were calculated using bootstrapping with 1,000 repetitions. From early adulthood to middle age Within PLCO, we assessed the population-statified and sex-stratified association between the standardized PGSLC (using linear combination weights from the UKBB most closely corresponding to each testing population) and per-5-year change between ages 20 and 50 in weight and BMI, with and without adjustment for the initial measurement at age 20. These analyses were additionally adjusted for birth year, sex (where appropriate) and principal components. We calculated the population-stratified AUC of the PGS for obesity outcomes at age 50. For this, we ran models including (i) birth year and sex, (ii) birth year, sex, principal components and PGSLC, (iii) birth year, sex, principal components and BMI at age 20 and (iv) birth year, sex, principal components, BMI at age 20 and PGSLC. We separately ran model (iv) when including an interaction term between the PGS and BMI at age 20. Based on evidence for statistical interaction between the PGS and BMI at age 20 for predicting obesity at age 50 across mul- tiple populations (Supplementary Table 16), we stratified our analyses on the presence of overweight or obesity at age 20 and, addition- ally, on sex. Confidence intervals (95%) for AUC were calculated using DeLong’s method. PGS and weight change due to ILIs Although neither intervention nor comparison arms were identical across DPP and Look AHEAD, both intervention arms were aimed at 7% weight loss while focused on the same process features83, and both represent a large shift in lifestyle behavior relative to the comparison arms. As such, we decided to pool study-specific effect estimates via inverse-variance weighted meta-analysis. In each study, we ran analyses after pooling the three largest popula- tion groups present in both trials: Black and/or African American, Hispanic and White (Supplementary Table 3). Population-stratified analyses were separately run as well. Within each study-specific population, we applied the linear combination weights for PGSLC most closely aligned with the target population (AFR, AMR and EUR, respectively). These scores were then standardized within the matching population, ignoring trial arm, whereafter we standard- ized again across all individuals for the population-pooled analyses. Due to restricting analyses to genotyped individuals from the three largest population groups, trial randomization was, by definition, broken. To investigate potential shifts in the PGS, we plotted its dis- tribution by trial arm, which showed minimal shifts in distribution (Extended Data Fig. 7). To investigate weight change, we focused on annual weight meas- urements. The weight loss nadir in both trials is known to occur at the 1-year mark, after which many individuals start regaining weight. As such, we separately examined the association of the PGS with (i) weight at year 1 (adjusting for baseline weight) and (ii) repeated weight measurements beyond year 1 up to year 4 (adjusting for weight at year 1) in the subset of individuals who had lost ≥3% of their initial body weight in the first year. Analyses were run by trial arm using linear mixed mod- els with random intercepts, with additional covariates being age, sex, principal components, the initial weight measurement (baseline or year 1) and random slopes for time (years). In addition, we ran trial–arm combined models in which we examined interaction effects between trial arm and PGS. These interaction terms are our main estimates of interest, as they reflect how genetic predisposition to obesity modi- fies the intervention’s effect on weight change, relative to the com- parison arm. Study-specific main and interaction effect estimates were separately pooled by means of inverse-variance weighted fixed-effect meta-analysis. Participant characteristics are presented in Supple- mentary Table 4. Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z Data availability The PGS variant-level weights for the GIANT-only and GIANT+23andMe multi-ancestry PGSs are available for download through the PGS Cata- log (https://www.pgscatalog.org/, publication ID PGP000724, score IDs PGS005198–PGS005204). The source data of the figures are provided in the supplementary tables. This research has been conducted using UKBB research under application number 1251. The UKBB genotype and phenotype data are available through the UKBB at https://www. ukbiobank.ac.uk. Pan-UKBB relatedness and ancestry determina- tions can be obtained via UKBB return 2442. Due to US Department of Veterans Affairs (VA) regulations and our ethics agreements, the analytic datasets used for this study are not permitted to leave the Million Veteran Program (MVP) research environment and the VA firewall. This limitation is consistent with other MVP studies based on VA data. However, the MVP data are made available to researchers with an approved VA and MVP study protocol. Information regarding access to the BioMe Biobank is available at https://icahn.mssm.edu/research/ ipm/programs/biome-biobank. For access to the Uganda GPC-UGR data, contact should be made to the director of the MRC/UVRI & LSHTM Uganda Research Unit, Entebbe, by email to mrc@mrcuganda.org. The data underlying this article are available upon reasonable request to the PLCO Cancer Data Access System: https://cdas.cancer.gov/plco/. Requests from researchers to access ALSPAC data and samples are welcomed; relevant procedures can be found at https://www.bristol. ac.uk/alspac/researchers/access/. Data from the Diabetes Prevention Program (V9) (https://doi.org/10.58020/3hw5-cf91) reported here are available for request at the NIDDK Central Repository (NIDDK-CR) website, Resources for Research (R4R) (https://repository.niddk.nih. gov/). The Diabetes Prevention Program genotype data were down- loaded from the dbGaP website under phs000681.v2.p1. Researchers can access data from the primary Look AHEAD data trial on the NIDDK repository. Due to limitations specified in informed consent, the Look AHEAD genetic data are not publicly available. Code availability We used publicly available software tools for all analyses. These soft- ware tools are listed in the main text and in the Methods. 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Factors associated with early adiposity rebound. ALSPAC Study Team. Pediatrics 105, 1115–1118 (2000). Acknowledgements We acknowledge the participants in each cohort contributing to this study. Additional acknowledgements are provided in the Supplementary Note. Support for title page creation and format was provided by AuthorArranger (https://authorarranger.nci.nih.gov/), a tool developed at the National Cancer Institute. This research was supported by the following funding bodies, which had no role in study design, data collection and analysis, preparation of the manuscript or decision to publish. US National Institutes of Health (NIH): 01HG006934-01 (G.R.A.), 1 U19 CA148537-01, 1K08 HG010155 (A.V.K.), 1RC2 MH089951, 1RC2 MH089951-01, 1RC2 MH089995, 1U01 HG011717 (S.F.), 1U01 HG011719 (A.V.K.), 1U01 HL172180 (S.F.), 1U19 CA148065, 1U19 CA148112, 1U19 CA148537, 5-P60-AR30701, 5-P60-AR49465, 5UM1 CA182883, 75N92020D00001, 75N92020D00002, 75N92020D00003, 75N92020D00004, 75N92020D00005, 75N92020D00006, 75N92020D00007, 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005, 75N92021D00006, AA-00145, AA-09203, AA-12502, AA009367, AA014041, AA07535, AA10248, AA13320, AA13321, AA13326, AA15416, AG000513, CA047988 (J.E.Bu.), CA054281, CA063464, CA098758, CA141298, CA164973, DA005147, DA036216, DA037904, DA044283, DA12854, DK056350, DK063491, DK078150, DK125187 (Y.V.S.), DK56990, DK56992, DK57002, DK57008, DK57078, DK57131, DK57135, DK57136, DK57149, DK57151, DK57154, DK57171, DK57177, DK57178, DK57182, DK57219, ES010126, EY014684, EY014684-03S1, EY014684-04S1, Fogarty grant D43 TW009077, HG011052 (X. Zhu), HHSC268200782096C, HHSN268200625226C, HHSN268200782096C, HHSN268200800007C, HHSN2682009600 09C, HHSN268201200008I, HHSN268201200036C, HHSN2682013 00001I/N01-HC-65233, HHSN268201300002I/N01-HC-65235, HHSN268201300003I/N01-HC-65236, HHSN268201300004I/N01- HC-65234, HHSN268201300005I/N01-HC-65237, HHSN26820150 0001I, HHSN268201500003I, HHSN268201700001I, HHSN268201 700002I, HHSN268201700003I, HHSN268201700004I, HHSN268 201700005I, HHSN268201800001C, HHSN268201800003I, HHSN268201800004I, HHSN268201800005I, HHSN268201800006I, HHSN268201800007I, HHSN268201800010I, HHSN268201800011I, HHSN268201800012I, HHSN268201800013I, HHSN268201800014I, Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z HHSN268201800015I, HHSN271201100005C, HHSN271201200022C, HL043851 (J.E.Bu.), HL046389 (Su.R.), HL080467 (J.E.Bu.), HL085144, HL113338 (Su.R.), HL129982 (H.M.H.), HL154996, HL54471, HL54472, HL54473, HL54495, HL54496, HL54509, HL54515, intramural project number 1Z01-HG000024 (F.S.C.), K01 HL135405 (B.E.C.), K02 AA018755, K05 CA175147, K99/R00 HL130580 (A.E.J.), KL2 RR024990, KL2 TR002490 (L.M.R.), N.1-AG-1-1, N.1-AG-1-2111, N01-AG-1-2100, N01-AG-1-2109, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, N01-HC-25195, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, N01-HD-1-3228, N01-HD-1-3329, N01-HD-1-3330, N01-HD-1-3331, N01-HD-1-3332, N01-HD-1-3333, N01-HG-65403, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N02-HL-64278, National Institute on Aging Intramural Research Program (E.M.S.), NR013520 (Y.V.S.), P01 CA055075, P01 CA87969, P30 AG10161, P30 AG72975, P30 DK072488, P30-CA015704, P30AR072580, P50 GM115305, R01 24799, R01 AG023629, R01 AG028050, R01 AG034454, R01 AG056477 (M.Ki.), R01 AG065357, R01 AG17917, R01 AG30146, R01 CA056678, R01 CA080122, R01 CA082664, R01 CA092579, R01 CA128813 (J.Y.P), R01 CA128978, R01 CA144034, R01 CA148677, R01 CA15847, R01 CA49449, R01 CA55069, R01 CA64277, R01 CA67262, R01 CA80205, R01 D0042157-01A, R01 D0042157-01A1, R01 DA042755, R01 DK053591, R01 DK062370 (M.B.), R01 DK066358, R01 DK072193 (CHNS, E.P.W., K.L.M.), R01 DK075787 (J.N.H., R.J.F.L., DGI), R01 DK087914, R01 DK089256 (C.-T.L., X.D., FamHS), R01 DK092127-04, R01 DK101855, R01 DK104371, R01 DK107786 (R.J.F.L.), R01 DK110113 (R.J.F.L.), R01 DK118011 (C.N.S.), R01 DK118427, R01 DK122503 (A.E.J., C.-T.L., G.C., K.E.N. and Q.M.), R01 DK124097 (R.J.F.L.), R01 DK135938 (A.E.J. and Y.L.), R01 DK136671 (C.N.S.), R01 DK139598 (K.E.N.), R01 EY022310, R01 HD056465 (S.F.A.G., CHOP), R01 HD074711, R01 HD100406, R01 HD30880, R01 HD58886, R01 HG003054, R01 HG010297 (R.J.F.L. and V.L.B.), R01 HG011035, R01 HL046380, R01 HL053353, R01 HL074166, R01 HL085251, R01 HL086694, R01 HL086718, R01 HL087641, R01 HL087652, R01 HL087660, R01 HL091357, R01 HL09135701, R01 HL092577 (P.T.E.), R01 HL095056, R01 HL103612, R01 HL104135, R01 HL105756, R01 HL108427, R01 HL111249, R01 HL111249-04S1, R01 HL113338, R01 HL117078, R01 HL119443, R01 HL120393, R01 HL139731 (S.A.Lu.), R01 HL142302 (K.E.N. and R.J.F.L.), R01 HL151152 (K.E.N., R.J.F.L. and V.L.B.), R01 HL156991 (K.E.N.), R01 HL157635 (P.T.E. and S.A.Lu.), R01 HL158884 (Y.L.), R01 HL160689 (R.W.M.), R01 HL163262 (K.E.N.), R01 HL163262-01A1 (M.Gr.), R01 HL172803, R01 HL177209 (P.T.E.), R01 HL77398, R01 MH081802, R01 MH58799-03, R01 NR012459, R01 NS032830, R01 NS100178 (J.W.C.), R01 NS105150 (J.W.C.), R01 NS114045 (J.W.C.), R01 NS45012, R03 HL154284 (B.E.C.), R21 DK105913, R35 CA53890, R35 HL135818 (Su.R., CFS), R35 HL135824 (C.J.W.), R37 HL045508, R56 HL150186 (Y.L.), RC2 AG036495, RC2 GM092618, RC4 AG039029, RF1 AG15819, RR020649, S10OD017985, S10OD026880, S10OD030463, S10RR025141, T32 HL007055 (H.M.H.), T32 HL129982 (L.M.R.), TW005596, U01 167552, U01 AG009740, U01 AG023746, U01 CA176726, U01 CA188392, U01 DK062418, U01 DK105535, U01 DK105556, U01 HG004402, U01 HG004423, U01 HG004436, U01 HG004438, U01 HG004446, U01 HG004798, U01 HG006378, U01 HG007416 (K.E.N.), U01 HG011723 (R.J.F.L.), U01 HL054457, U01 HL054464, U01 HL054481, U01 HL054512, U01 HL080295, U01 HL130114, U01 HL54498, U01 HL54527, U01 NS069208-01, U01AG46152, U01AG61256, U01HG006379, U01HG008657, U01HG008664, U01HG008666, U01HG008672, U01HG008673, U01HG008676, U01HG008679, U01HG008680, U01HG008684, U01HG008685, U01HG008701, U10 CA37429, U19 AG063893, U19 CA148065, U19 CA148537, U19 HL065962, U24 MH068457-06, U54MD007593, UL1 RR024975, UL1 TR000077, UL1 TR000445, UL1 TR001878, UL1 TR001881, UL1 TR002243, UL1 TR004419, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1RR025005, UL1TR001881, UM1 CA182876, UM1 CA182910, UM1 CA182913 (J.E.Bu.), UM1 CA186107, UM1 DK126194 (S.F.A.G.), X01 HG007492, Z01 CP010119, ZIA CP010152-20. The European Union: EMBO 3573 (Kr.L.), ERDF European Regional Development Fund 539/2010 A31592, European Regional Development Fund (Kr.L.), 018996, EUROSPAN (LSHG-CT-2006-018947), 223004, HEALTH-F4-2007-201413 by the European Commission (QLG2-CT-2002-01254), EUROHEADPAIN (602633), HEALTH-F4-2007-9602768, HEALTH-F2-2009-223175, EpiMigrant, 279143, RiskyCAD (305739), HEALTH-F2-2013-601456 (CVGenes@ Target), research and innovation programme (G.E.D.), EU H2020 Marie Sklodowska-Curie grant agreement no. 786833 (J.R.), EU H2020 research and innovation programme (634935 and 633784), EU H2020 TO_AITION 848146 (S.W.v.d.L.), EU H2020 (iHealth-T2D, 643774), EU H2020 (755320 for TAXINOMISIS and 848146 for To Aition), EU H2020 contract no. 733100 (P.C.), 2014-2020.4.01.16-0125 (A.M), EU HORIZON NextGen 101136962 (S.W.v.d.L.), EU HORIZON MIRACLE 101115381 (S.W.v.d.L.), LSHM-CT-2007-037273, the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115317 (DIRECT), the Innovative Medicines Initiative 2 Joint Undertaking 115974, the ERA-Net Cofund action no. 727565, MAESTRIA 965286 (P.T.E and, P.Ki.), the European Social Fund (M.S.-L.), SOC 95201408 05F02, the European Community (SOC 98200769 05F02), QLG1-CT-2001-01252, the European Science Foundation (EuroSTRESS project FP-006), EU pBETTER4U_EU 101080117, LSHM-CT-2006-037593, EXGENESIS, European Commission 018947 (LSHG-CT-2006-01947), EHRA-PATHS (945260). The UK National Institute for Health Research (NIHR) Centers: RP-PG-0407-10371, the NIHR Biomedical Research Centre at the Institute of Cancer Research, the NIHR Cambridge Biomedical Research Centre, NIHR Cardiovascular Biomedical Research, NIHR Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the NIHR Exeter Clinical Research Facility, the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards, the NIHR Leicester Cardiovascular Biomedical Research Centre (BRC-1215-20010) (C.P.N., P.S.B. and N.J.S.), the NIHR Manchester Biomedical Research Centre (K.M. and A.L.), the NIHR Official Development Assistance (ODA, 16/136/68), the NIHR Oxford Biomedical Research Centre, the NIHR to the Biomedical Research Centre at the Institute of Cancer Research and Royal Marsden Foundation NHS Trust, the NIHR-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London (TwinsUK and M.M.), the UK National Institute for Health Research Academic Clinical Fellowship (S.J.H.), University of Bristol NIHR Biomedical Research Centre (BRC-1215-2001) (N.J.T.). Netherlands Organization for Scientific Research (NWO): NWO 175.010.2003.005, NWO 480-05-003, NWO 481-08-013, NWO 481-11-001, NWO Gravitation 024.001.003, NWO Vi.C.191.021, NWO Vici 016.130.002, 453-16-007/2735, NWO/SPI 480-15-001/674, NWO/SPI 56-464-14192, 10-000-1002, 911-03-012, 175.010.2005.011, NWO Division for the Social Sciences (MaGW) VIDI 016-065-318 (D.P.), the Netherlands Genomics Initiative (NGI)/NWO Netherlands Consortium for Healthy Aging (NCHA) 050-060-810, NGI/NWO - the Consortium for Systems Biology (NCSB), the Center for Medical Systems Biology (CSMB, NWO Genomics), The Netherlands Organization for Health Research and Development (ZonMw) 6130.0031, NWO/ZonMw Rubicon grant 452182321 (R.A.J.S.), ZonMW 100-001-004, ZonMW 261-98-710, ZonMW 60-60600-97-118, ZonMW 636340002, ZonMW 916.19.151 (H.H.H.A.), ZonMw 95103007, the Dutch Research Council (Vidi Innovational Research Award 016.096.309), Medical Research Council program GB-MW 940-38-011. UK Medical Research Council (MRC): G0000934, G0601966, G0700931, G1001799, G9521010D, K013351, MC_PC_13046, MC_PC_13049, MC_U137686851, MC_ UU_00007/10 (V.V. and A.F.W.), MC_UU_00017/1, MC_UU_12015/1, MC_ UU_12026/2, MC-PC-14135, MR/M016560/1, MR/N013166/1 (K.A.K.), Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z MRC Integrative Epidemiology Unit MC_UU_00011/1 (N.J.T. and R.E.Mi.), National Health and Medical Research Council Leadership Investigator GNT 2025349 (E.Hy.), R024227 (M.Ki.), the Medical Research Council Doctoral Training Programme in Precision Medicine (MR/N013166/1) (P.R.H.J.T.), the MRC-PHE Centre for Environment and Health, the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement (GPC-UGR), the UKRI Medical Research Council MC_UU_00019/1, the UKRI Medical Research Council MR/Y014022/1 (A.W., N.C.), U.MC_UU_00007/10, Y014154 (M.Ki.). Wellcome Trust: 068545/Z/02, 072960/Z/03/Z, 076113, 076113/B/04/Z, 084723/Z/08/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/B/08/Z, 085475/Z/08/Z, 088158/Z/09/Z, 090532, 090532/Z/09/Z, 098051, 098381, 104036/Z/14/Z, 104085/Z/14/Z, 106130, 201543/B/16/Z, 202922/Z/16/Z, 203141, 203141/Z/16/Z, 212259, 212904/Z/18/Z, 212946/Z/18/Z, 216767/Z/19/Z, 217065/Z/19/Z (N.J.T.), 220740/Z/20/Z (S.F.), 221854/Z/20/Z (M.Ki.), Institutional Strategic Support Fund (204813) (K.H.W.), the NIHR/Wellcome Trust Imperial Clinical Research Facility, Wellcome Trust Investigator 202802/Z/16/Z (N.J.T.), Wellcome Trust Strategic Award (079895), WT095219MA, WT098051. The Novo Nordisk Foundation (NNF): 12955 (B.F.), NNF NNF20OC0062294 (Tu.K.), NNF15OC0015896, NNF18CC0034900 (M.R.C., N.G., R.J.F.L. and T.O.K.), NNF22OC0074128 (T.O.K.), NNF20OC0059313 (R.J.F.L.), NNF23SA0084103 (M.R.C., N.G., R.J.F.L. and T.O.K.), grant NNF20SA0067242 from the Danish Cardiovascular Academy, which is funded by the Novo Nordisk Foundation (M.G.-M.), the Danish Diabetes Academy, Novo Nordisk Foundation, NNF17SA0031406 (M.R.C.), the TriPartite Immunometabolism Consortium (TrIC)-NNF NNF15CC0018486. Australian National Health and Medical Research Council (NHMRC): NHMRC Practitioner Fellowship GNT1103329 (A.W.H.), NHMRC Practitioner Fellowship GNT1154518 (D.A.M.), NHMRC Investigator Grant APP1172917 (S.E.M.), NHMRC Career Development Fellowship (J.B), 209057, 211069, 241944, 302010, 389875, 389891, 389892, 389938, 390130, 396414, 403981, 442915, 442981, 457349, 496688, 496739, 512423, 552485, 571013, 572613, 613601, 613672, 614296, 974159, 1009458, 1011506, 1021858, 1027449, 1044840, 1059711, 1074383, 1113400 (P.M.Vis.), 1186500 (D.F). Academy of Finland: 100499 (J.K.), 117797, 118555 (J.K.), 124243, 126925, 121584, 124282, 129378, 141054 (J.K.), 141071, 205585 (J.K.), 206374, 251360, 264146 (J.K.), 276861, 285547, 308248 (J.K.), 312073 (J.K.), 322098, 336823 (J.K.), 350426 (M.Ki.), 352792 (J.K.), 356405, 286284, 134309, 77299, Center of Excellence in Complex Disease Genetics (312062) (Sa.R.). Cancer Research UK (CRUK): C12292/A11174, C1281/A12014, C1287/A10118, C1287/A10710, C1287/A16563, C16077/A29186, C16913/ A6135, C490/A10124, C500/A16896, C5047/A10692, C5047/A1232, C5047/A15007, C5047/A3354, C5047/A7357, C5047/A8384, C8197/ A16565, C18281/A29019 (N.J.T.), RCCPDF\100007 (K.H.W.). The Swedish Research Council: 2016-06830 (G.H.), 2017-00641, 2021- 02273 (J.G.S.), grant for the Swedish Infrastructure for Medical Population-based Life-course Environmental Research – SIMPLER, Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039, the Swedish Heart-Lung Foundation (2022-0344 and 2023-03332) (J.G.S.). The Netherlands Heart Foundation: NHS2010B233, NHS2010B280, 2001 D 032 (J.W.J.), Dutch Heart Foundation (DHF) (P.Ki. and M.R.), RACE V (CVON 2014–9), RED-CVD (CVON2017-11), from Top Sector Life Sciences & Health to the Dutch Heart Foundation (PPP Allowance; CVON-AI (2018B017)), Dutch Heart Foundation and ZonMW 01-002-2022-0118 EmbRACE. The European Research Council (ERC): ERC-2011-StG 280559-SEPI, ERC-STG-2015-679242 (J.G.S.), ERC-230374, ERC-2017-STG-757364, ERC-CoG-2015-681466, ERC Grant 310644 MACULA, CoG- 2015_681742_NASCENT, ERC 742927. The British Heart Foundation (BHF): 32334, AA/18/2/34218 (P.Ki.), CH/1996001/9454, FS/14/66/3129 (O.G.), RG/14/5/30893 (Pa.D.), RG/17/1/32663, SP/04/002, SP/16/4/32697 (C.P.N), the British Heart Foundation Centre for Research Excellence (H.W.). German Research Foundation (Deutsche Forschungsgemeinschaft (DFG)): 209933838 – SFB 1052; B03, C01; SPP 1629 TO 718/2- 1, 387509280 – SFB 1350 (I.M.H.), 431984000 - SFB 1453 (M.Wu.), BR 6028/2-1 (Ca.B), DFG BO 3815/4-1 (I.M.H., C.A.B.), HE 3690/7-1 (I.M.H), Ki 509167694 (P.Ki.). German Research Council (DFG): EI 969/2-3, ER 155/6-1;6-2, HO 3314/2-1;2-2;2-3;4-3, INST 58219/32-1, JO 170/8-1, KN 885/3-1, PE 2309/2-1, SI 236/8-1;9-1;10-1. The American Heart Association (AHA): 15GRNT25880008, 15POST24470131 (C.N.S.), 17IBDG33700328 (J.W.C.), 15GPSPG23770000 (J.W.C.), 17POST33650016 (C.N.S.), 18SFRN34250007 (S.A.Lu.), 961045 (P.T.E.). The American Diabetes Association (ADA): Jr Faculty Development 11-22-JDFPM-06 (C.N.S.), 11-23-PDF-35 (A.H.-C.). German Federal Ministry of Education and Research (BMBF): 01ZZ0103, 01ZZ0403, 01ZZ9603, 03IS2061A, 03ZIK012, BMBF 01EA1801A, BMBF 01ER0804 (K.-U.E.), BMBF 01ER1206, BMBF 01ER1507 (I.M.H.). German Ministry of Education and Science: 01EG0401, 01ER1001D, 01GI0205, 01GI0856, 01GI0860, 01GS0820_WB2-C, the Federal Ministry of Science, Germany (01 EA 9401). Australian Research Council (ARC): DP0770096, DP1093502, FL180100072 (P.M.Vis.), FT220100069 (Lo.Y.). The US Department of Veterans Affairs: Baltimore Geriatrics Research, Education, and Clinical Center, Merit Grant BX004821, BX003340, BX003362 and BX005831, I01-BX004821 (MVP 001, P.W.F.W. and Kelly Cho). Additional funding came from the following sources. ‘Indremedisinsk Forskningsfond’ at Bærum Hospital; 23andMe; a Royal Society URF (J.F.W.); Abbott; Accare Centre for Child and Adolescent Psychiatry; ADAS software (S.N.); AFNET; Agence Nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travail (ANSES); AICR Netherlands A10-0227; Amgen (P.M.R. and D.I.C.); Amsterdam Public Health (APH); Arthritis Research UK; Astellas Pharma, Inc.; AstraZeneca; Avera Institute for Human Genetics; Bayer Pharma AG; Beijing Municipal Center for Disease Prevention and Control; Beijing Municipal of Health Reform and Development Project no. 2019-4 (Beijing Eye Study); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), CP 32; Biosense Webster (S.N.); Boston University Chobanian & Avedisian School of Medicine; Bristol Myers Squibb; Budgetary funds from the National Institute for Health and Welfare (THL) of Finland; Business Finland through the Personalized Diagnostics and Care program coordinated by SalWe Ltd. (3986/31/2013); California Cancer Research Fund 99-00527V-10182; Cancer Australia; Cancer Australia PdCCRS (J.B); Cancer Centre at Barts and QMUL (H.R.W.); Cancer Council Queensland (J.B); Cancer Council Tasmania; Cancer Councils of Victoria and South Australia; Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6); Chinese National Human Genome Center at Shanghai; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (X51001); Concerted Research Action of the KU Leuven (GOA/15/017) (F.C. and S.J.); Council of Scientific and Industrial Research (CSIR), Government of India, grant no. BSC0122; Curtin University; D70-RESRICGIROTTO (G.G.); Daiichi Sankyo Co., Ltd.; Danish Ministry of Internal Affairs and Health; Dell Loy Hansen Heart Foundation (M.J.Cu.); Department of Biotechnology, Government of India (C.S.Y.); Department of Science and Technology, Government of India through PURSE II CDST/SR/ PURSE PHASE II/11 provided to Jawaharlal Nehru University; Departments, Division and the Board of Directors of the Leiden University Medical Centre; Dutch Ministry of Economic Affairs, Agriculture and Innovation (project KB-15-004-003); Edith Cowan University; EFPIA companies; EHRA; Erasmus MC, Rotterdam; Estonian Research Council PUT 1371 (Kr.L.), PUT PRG1291 (T.E); Finska Läkaresällskapet (E.W.); Fondation ARC; Fondation de France; Fondazione di Sardegna (U1301.2015/AI.1157. BE Prat. 2015-1651); Fondo Sectorial de Investigación en Salud y Seguridad Social (SSA/ IMSS/ISSSTE CONACYT, project 150352) in Mexico; Foundation for the National Institutes of Health through the Accelerating Medicines Partnership (no. HART17AMP) and the Parelsnoer Initiative (PSI); Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z Foundation Leducq: ‘PlaqOmics’ and ‘AtheroGen’, 24CVD01 (P.T.E.); Funding Program for Next-Generation World-Leading Researchers (NEXT Program, no. LS056).; FWO Vlaanderen (G.0684.12N and G.0830.13N) (F.C. and S.J.); Generalitat de Catalunya; Genome Quebec and Genome Canada (G.L.); German Cancer Aid (70-2488-Ha I, ULM); German Centre for Cardiovascular Research (DZHK): FKZ 81×2800182 (P.Ki.), FKZ 81Z0710116 (P.Ki.), FKZ 81Z0710110 (P.Ki.); GlaxoSmithKline; governmental funding of clinical research within the Swedish National Health Service (J.G.S.); Greek Secretariat for Research and Technology (Cooperation 890/2009); Health Care Centers in Vasa, Närpes and Korsholm; Health~Holland PPP Allowance ‘Getting the Perfect Image’ (S.W.v.d.L.); Heinz Nixdorf Foundation; Helmholtz Zentrum München– German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria; Hjartavernd (the Icelandic Heart Association); Hong Kong Kadoorie Charitable Foundation; ImriCor (S.N.); Institut National du Cancer (INCa); Instituto de Salud Carlos III: CPII22/00007 (M.S.-L.), FEDER (PI08/1770, PI09/00773-Cantabria, PI11/01889-FEDER, PI12/00265, PI12/01270, PI12/00715, PI15/00069, RD09/0076/00036); Italian Ministry of Health and the US National Institute on Aging (263 MD 9164 and 263 MD 821336); Italian Ministry of Health through RC 01/21 (M.P.C.).; Juvenile Diabetes Research Foundation International (JDRF) (BEAT-DKD); Komen Foundation for the Cure; Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065); Korea National Institute of Health intramural grant 2019-NG-053-02; Kuwait Foundation for the Advancements of Sciences (KFAS) (T.A.T. and F.A.-M.); Leiden University Medical Center; Leo Laboratories; Ligue départementale du Val de Marne; Ligue Nationale Contre le Cancer; Medical University of Graz (ASPS); Merck Sharp & Dohme Corp.; MEXT (16H05250, 15K19242, 16H06277, 19K19434, 20K10514, 21H03206, 22H04923, 22H03350, 23K24608, 24K02690); Mitsubishi Tanabe Pharma Corporation; Murdoch University; National Institute of Health, Republic of Korea (2022-NI- 067-02); National Institute of Health, Republic of Korea (4845–301, 4851–302, 4851–307); National Key Research and Development Program of China (2016YFC 0900500, 0900501, 0900504, 1303904); National Research Foundation of Korea (NRF): RS-2023-00245960 (Y.S.C.), NRF-2023R1A2C2006416 (H.-N.K.); NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Netherlands Twin Registry Repository and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI–NL, 184.021.007 and 184.033.111); Neuroscience Campus Amsterdam (NCA); NextGenerationEU Project code CN_00000033, CUP B83C22002930006; Nordic Center of Excellence in Health-Related e-Sciences (Xueping.L.); Novartis Institute for Biomedical Research; Novo Nordisk, Inc.; NZO (Dutch Dairy Association); Oak Foundation fellowship (B.F.); Otsuka Pharmaceutical Co., Ltd.; Pfizer; philanthropic donation to Northshore University Health System; Pla Director d’Oncologia de Catalunya (XBTC); Prostate Cancer Canada Movember Discovery Grant (D2013- 17) (RJH); Prostate Research Campaign UK (now PCUK/Prostate Action); Queen’s University Belfast; Region of Southern Denmark; Research Foundation of Copenhagen County; Research Project for Excellence IKY/SIEMENS; Rosetrees Trust; Royal Marsden Foundation NHS Trust; Safe Work Australia, WA Health, Government of Western Australia (WADOH) (Future Health WA G06302); Sanofi; Sardinian Autonomous Region (L.R. no. 7/2009) cRP3-154; Servier Research Group; Shanghai Municipal Science and Technology Major Project (2017SHZDZX01); Siemens Healthineers; Social Sciences Council medium-sized investment grants GB-MaGW 480-01-006 and GB-MaGW 480-07-001; Social Sciences Council project grants GB-MaGW 452-04-314 and GB-MaGW 452-06-004; Special Governmental Grants for Health Sciences Research, Turku University Hospital; Stanley Medical Research Institute; Taisho Pharmaceutical Co., Ltd.; Takeda Medical Research Foundation; Takeda Pharmaceutical Co., Ltd.; Temas Prioritarios de Salud Instituto Mexicano del Seguro Social (2014-FIS/IMSS/PROT/PRIO/14/34); the Aarhus and Copenhagen universities and university hospitals; the Accelerating Clinical Trials funding stream in Canada (P.Ki.); the Agency for Science, Technology and Research, Singapore; the ALF/ LUA research grant in Gothenburg; the Althingi (the Icelandic Parliament); the Amsterdam University Medical Center, location VUmc; the Anthony DeNovi Fund; the Assessorato Ricerca Regione Campania (POR CAMPANIA 2000/2006 MISURA 3.16); the Atlantic Philanthropies; the Augustinus Foundation; the Augustinus Foundation; the Austrian Ministry of Science; the Austrian National Bank Anniversary Fund, P15435; the Austrian Science Fond (FWF) P20545-P05, P13180, P20545-B05; the Baden Württemberg Ministry of Science, Research and Arts; the Becket Foundation; the Belgian federal government (National Cancer Plan KPC_29_023) (F.C. and S.J.); the Biomedical Research Council (BMRC) of Singapore (08/1/35/19/550, 09/1/35/19/616); the Breast Cancer Research Foundation; the Broad Institute; the C.G. Sundell Foundation; the Canada Research Chair Program (G.L.); the Canadian Cancer Society Research Institute (2013-702108) (RJH); Cancer Foundation Finland; the Catalan Government DURSI 2009SGR1489; the Center for Translational Molecular Medicine; the Center of Innovation Program, the Global University Project from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Centre for Ageing Research and Development in Ireland; the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710); the Children’s Hospital of Philadelphia; the Children sʼ Hospital of Philadelphia Endowed Chair in Genomic Research; the China-Japan Friendship Hospital, Ministry of Health for support for CHNS 2009; the CNR project FOE-2021 DBA. AD005.225 NUTRAGE; the Competitive Research Funding of the Tampere University Hospital (9M048, 9N035); the Consejo Nacional de Ciencia y Tecnología (CONACYT) in Mexico (2092, M9303, F677, 251); the Core Research for Evolutional Science and Technology (CREST) from the Japan Science Technology Agency; the Cotswold Foundation; the Council of Scientific and Industrial Research, Indian Ministry of Science and Technology (G.R.C.); the Daniel B. Burke Endowed Chair for Diabetes Research (S.F.A.G., CHOP); the Danish Centre for Health Technology Assessment; the Danish Diabetes Association; the Danish Heart Foundation (M.G.-M., Inter99); the Danish National Research Foundation; the Danish Pharmaceutical Association; the Danish Pharmacists’ Fund; The Danish Research Council for Independent Research; the Department of Innovation, Research, and University of the Autonomous Province of Bolzano-South Tyrol; the Diabetes Research Foundation of Finnish Diabetes Association; the Donald C. McGraw Foundation; the Dutch Brain Foundation; the Dutch Kidney Foundation (grant E0.13); the Dutch Ministry of Justice (WODC); the Economic and Social Research Council (ESRC) UK: ES/H029745/1, ES/L008459/1, ES/M001660/1, ES/ S007253/1 (M.Ku.), ES/T002611/1 (M.Ku.), ES/T014083/1 (M.Ku.); the Egmont Foundation; the Elizabeth Blackwell Institute for Health Research, University of Bristol (K.H.W.); the Else Kröner-Fresenius-Stiftung: P.Ki., 2012_A147; the Emil Aaltonen Foundation; The Everyman Campaign; the Eye Birth Defects Foundation, Inc.; the Faculty of Biology and Medicine of Lausanne; the Federal State of Mecklenburg-West Pomerania; the Finnish Cardiac Research Foundation; the Finnish Cultural Foundation; the Finnish Diabetes Research Foundation; the Finnish Foundation for Cardiovascular Research (Ve.S. and Sa.R.); the Finnish innovation fund Sitra (E.W.); the Finnish Medical Society; the Finnish Ministry of Education and Culture; the Finnish Society of Clinical Chemistry; the Folkhälsan Research Foundation; the Foundation for Pediatric Research, Finland; the Foundation for Strategic Research and the Stockholm County Council (560283); the Free State of Saxony; the French Ministry of Research; the Fundación IMSS Mexico; the Fundación Marqués de Valdecilla (API 10/09); the FWO (TVDB); the Galician Foundation of Genomic Medicine; the General Clinical Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z Research Center Program (GCRC); the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health; the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; the German Heart Foundation (DSF); the German Ministry of Cultural Affairs; Gothenburg University; the Government of Canada through Genome Canada, Genome Québec, the Canadian Institutes of Health Research (CIHR): FRN-CCT-83028, GPH-129344, MOP-82893, operating grants (E.J.P.) and a New Investigator Award (E.J.P.), PJT no. 156248 (G.L.)., the Department of Defence (W81XWH-10-1-0341), the Ministère de l’Économie et de l’Innovation du Québec, the Ministère de l’Économie, Science et Innovation du Québec, the PSRSIIRI-701 grant.; grant of the National Center for Global Health and Medicine (NCGM); the Gratama Foundation; the Greek General Secretary of Research and Technology (PENED 2003); the Health and Social Care Research and Development Division of the Irish Public Health Agency; the Health Fund of the Danish Health Insurance Societies; the Helsinki University Central Hospital Research Foundation; the Ib Henriksen Foundation; the Italian Ministry of Education, University and Research (MIUR) 5571/ DSPAR/2002; the Italian Ministry of Universities; the Jan Dekker Foundation; the Japan Agency for Medical Research and Development (AMED): the Program for an Integrated Database of Clinical and Genomic Information (kk0205008), the Practical Research Project for Rare/Intractable Diseases (ek0109070, ek0109283, ek0109196, ek0109348); the Juho Vainio Foundation (Ve.S., YFS); the KfH Foundation for Preventive Medicine (the KfH Stiftung Präventivmedizin); the KfH Stiftung Präventivmedizin e.V. (C.A.B.); the Kids Research Institute Australia; the Knut and Alice Wallenberg Foundation; the Leiden University, Research Profile Area ‘Vascular and Regenerative Medicine’; the Leipzig Research Center for Civilization Diseases (LIFE); the Lundbeck Foundation (R155-2013-14070); the Lundberg Foundation; the March of Dimes Birth Defects Foundation; the Medical Research Council of Canada; the Ministry of Innovation, Science, Research and Technology, North Rhine-Westphalia (MIWFT-NRW); the Montreal Heart Institute Biobank; the Montreal Heart Institute Foundation (G.L.); the Morris and Horowitz Families Endowed Professorship; the Movember Foundation grant no. D2013-36; the Municipal Health Care Center and Hospital in Jakobstad; the Närpes Health Care Foundation; the National Cancer Research Institute (NCRI) UK; the National Cancer Research Network UK; the National Health Research Institutes, Taiwan (MG-112-SP-09, MG-112-PP-18, MG-113-GP-03); the National Natural Science Foundation of China (81970684, 91846303); the National Recovery and Resilience Plan (NRRP), European Union; the National Research Foundation, Singapore (HUJ-CREATE Programme 370062002); the National Science Council, Taiwan (NSC 98-2314-B-075A-002-MY3); the National University Health System, Singapore; the National University of Singapore; the Netherlands Cardiovascular Research Initiative (DECISION project 848090001); the Nordic Center of Excellence in Disease Genetics; the Norwegian Atrial Fibrillation Research Network; the Office of Research on Minority Health (ORMH); the Office of the First Minister and Deputy First Minister of Ireland; the Ollqvist Foundation; the Oogfonds, MaculaFonds, Landelijke Stichting voor Blinden en Slechtzienden, Stichting Blindenhulp, Stichting A.F. Deutman Oogheelkunde Researchfonds; the Orchid Cancer Appeal; the Oulu University Hospital, 24301140; the Ovarian Cancer Research Fund; the Paavo Nurmi Foundation; the Perelman School of Medicine at the University of Pennsylvania; the Perklén Foundation; the Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); the Prostate Cancer Foundation of Australia; the Prostate Cancer Research Foundation; the Quebec Breast Cancer Foundation; the Raine Study Medical Research Foundation; the Republic of Croatia Ministry of Science, Education and Sports grant 108-1080315-0302 (I.R.); the Research Council of Norway (287086); the Research Institute for Diseases in the Elderly (014-93-015; RIDE2); the Robert Dawson Evans Endowment of the Department of Medicine at Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center; the Ronald and Rita McAulay Foundation; the Royal Marsden NHS Foundation Trust; the Science Foundation Ireland-Department for the Economy (SFI-DfE) Investigator Program Partnership Award (15/ IA/3152); the Scottish Funding Council (HR03006); the Signe and Ane Gyllenberg Foundation; the Sigrid Juselius Foundation; the Singapore Ministry of Health (Population Health Metrics and Analytics PHMA); the Singapore National Medical Research Council (NMRC): 1270/2010, 0796/2003, 1176/2008, 1149/2008, Singapore Translational Research Investigator (STaR) Award (NMRC/STaR/0028/2017) (J.C.C.), STaR/0003/2008, 1249/2010, CG/SERI/2010, CIRG/1371/2013, CIRG/1417/2015; the Skåne University Hospital; the Smilow family; the Social Insurance Institution of Finland; the Social Ministry of the Federal State of Mecklenburg-West Pomerania; the South-Eastern Norway Regional Health Authority (2019122); the Spanish Association Against Cancer (AECC) Scientific Foundation; the Spanish Ministry of Science and Innovation (CEX2018-000806-S); the St. Louis Men’s Group Against Cancer; the State of Brandenburg (DZD grant 82DZD00302); the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council; the Strategic Priority CAS Project (XDB38000000); the Swedish Cancer Foundation; the Swedish Foundation for Strategic Research (Dnr IRC15-0067); the Swedish Ministry of Education; the Swiss National Science Foundation (33CSCO-122661, 33CS30-139468, 33CS30-148401, 33CS30_177535, 3247730_204523 and 320030_220190); the Swiss Personalized Health Network (2018DRI01); the Taichung Veterans General Hospital, Taichung, Taiwan (TCVGH-1003001C); the Tampere Tuberculosis Foundation; the Tampere University Hospital Supporting Foundation; the Torsten and Ragnar Soderberg Foundation; the Turku University Foundation; the UKCRC Centre of Excellence for Public Health Northern Ireland; the University Hospital Regensburg; the University Medical Center Groningen; the University of Notre Dame Australia; the University of Oulu, 24000692; the University of Western Australia; the US Centers for Disease Control and Prevention (CDC): U01 DP003206; the US Centers for Disease Control and Prevention (CDC)/Association of Schools of Public Health: S043, S1734, S3486; the Victor Chang Cardiac Research Institute, NSW Health (D.F.); the Wellcome Trust/ Wolfson Foundation; the Yrjö Jahnsson Foundation; TrygFonden (7-11-0213); University of Helsinki HiLIFE Fellow and Grand Challenge grant (Sa.R.); the University of Michigan; the University of Newcastle; Vestre Viken Hospital Trust; VIAgenomics (SP/19/2/344612); VicHealth and Cancer Council Victoria; Vincent Fairfax Family Foundation; VU University Medical Center, Amsterdam; VU University’s Institutes for Health and Care Research (EMGO+); Wageningen University, Wageningen; Wake Forest School of Medicine grant M01 RR07122 and Venture Fund; Wellcome Trust Sanger Institute; and the Women and Infants Research Foundation. Author contributions Steering committee: G.R.A., T.L.A., S.I.B., M.B., D.I.C., T.E., T.M.F., J.N.H., G.L., C.M.L., A.E.L., R.J.F.L., K.L.M., K.E.N., C.J.O., Y.O., Y.V.S., U.T., P.M.Vis., R.G.W. and C.J.W. Conveners of GIANT working groups: S.I.B., Pa.D., J.N.H., A.E.J., G.L., C.M.L., A.E.L., R.J.F.L., E.M., K.L.M., K.E.N., Y.O., C.N.S., Sa.V., P.M.Vis., R.G.W., C.J.W., A.R.Wo. and Lo.Y. Writing group, coordination or supervision of data collection or analysis specific to the manuscript: J.D.A., S.I.B., M.R.C., S.F., S.E.G., J.N.H., Q.H., J.M.F., R.J.F.L., M.Nak., M.H.P., G.Ro., R.A.J.S., Y.V.S., N.J.T., K.H.W., Lo.Y. and X.Y. Data preparation group (checked and prepared data from contributing cohorts for GWAS meta-analyses): J.D.A., S.I.B., S.-H.C., T.F., M.Gr., Yi.J., Tu.K., Kr.L., M.Ma., D.E.M., C.M.-G., E.M., A.Moo., M.C.Y.N., A.E.L., A.E.J., Sa.V., C.N.S., Si.R., T.W.W., A.R.Wo, X.Y. and K.L.Y. Primary BMI working group: J.D.A., S.I.B., V.L.B., G.C., Pa.D., T.M.F., M.Gr., M.G.-M., J.N.H., A.E.J., A.E.L., R.J.F.L., Y.L., E.M., K.L.M., Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z K.E.N., Y.O., M.H.P., Sa.S., R.A.J.S., Y.V.S., E.P.W., C.J.W., Lo.Y., X.Y. and K.L.Y. All other authors were involved in the design, management, coordination or analysis of contributing studies. Consortium representatives: publication-review@23andme.com (23andMe Research Team); aejustice1@geisinger.edu (DiscovEHR); marylyn@ pennmedicine.upenn.edu (eMERGE); segun.fatumo@lshtm.ac.uk (GPC-UGR); practical@icr.ac.uk (PRACTICAL); mkumari@essex.ac.uk (Understanding Society Scientific Group); yan.v.sun@emory.edu (VA Million Veteran Program). Competing interests The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.I.McC. (since June 2019) and A.Mah (since January 2020) are employees of Genentech and holders of Roche stock. Yu.J., Ji.S. and Ad.A. are employed by and hold stock or stock options in 23andMe, Inc. S.W.v.d.L. has received Roche funding for unrelated work. M.J.Ca. is Chief Scientist for Genomics England, a UK Government company. P.S. has received research awards from Pfizer, Inc. D.H. is currently employed at Bristol Myers Squibb. G.C.-P. is an employee of 23andMe, Inc. Since completing the work contributed to this paper, D.J.T. has left the University of Cambridge and is now employed by Genomics plc. I.N. is an employee and stock owner of Gilead Sciences; this work was conducted before employment by Gilead Sciences. P.Ki. received research support for basic, translational and clinical research projects from the German Research Foundation (DFG), the European Union, the British Heart Foundation, the Leducq Foundation, the Else-Kröner-Fresenius Foundation, the Dutch Heart Foundation (DHF), the Accelerating Clinical Trials funding stream in Canada, the Medical Research Council (UK) and the German Center for Cardiovascular Research and from several drug and device companies active in atrial fibrillation and has received honoraria from several such companies in the past but not in the last 5 years. P.Ki. is listed as inventor on two issued patents held by the University of Hamburg (Atrial Fibrillation Therapy WO 2015140571 and Markers for Atrial Fibrillation WO 2016012783). M.R. received consultancy fees from Bayer (OCEANIC-AF national PI) and InCarda Therapeutics (RESTORE-SR national PI) to the institution, unrelated to this research/dataset. M.J.Cu. has served on advisory boards or consulted for Boston Scientific, Biosense Webster, Janssen Scientific Affairs and Johnson & Johnson. R.J.F.L. has acted as a member of advisory boards and as a speaker for Eli Lilly and the Novo Nordisk Foundation, for which she has received fees. S.N. is a scientific advisor to Circle software, ADAS software, CardioSolv and ImriCor and receives grant support from Biosense Webster, ADAS software and ImriCor. S.A.Lu. is an employee of Novartis. S.A.Lu. received sponsored research support from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Fitbit, Medtronic, Premier and IBM and has consulted for Bristol Myers Squibb, Pfizer, Blackstone Life Sciences and Invitae. P.T.E. receives sponsored research support from Bayer AG, Bristol Myers Squibb, Pfizer and Novo Nordisk; he has also served on advisory boards or consulted for Bayer AG. Her.S. has received honoraria for consulting from AstraZeneca, MSD/Merck, Daiichi, Servier, Amgen and Takeda Pharma. He has additionally received honoraria for lectures and/or chairs from AstraZeneca, BayerVital, BRAHMS, Daiichi, Medtronic, Novartis, Sanofi and Servier. S.E.G. is employed by Regeneron. C.J.W. is employed by Regeneron. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. K.S. is employed by deCODE Genetics/Amgen, Inc. Va.S. is employed by deCODE Genetics/ Amgen, Inc. G.T. is employed by deCODE Genetics/Amgen, Inc. U.T. is employed by deCODE Genetics/Amgen, Inc. E.Ba. is an employee of Empirico, Inc. Al.K. declares having received research grants through his affiliation from Novo Nordisk and Pharmaserve Lilly and consulting honoraria from Pharmaserve Lilly, Sanofi-Aventis, Novo Nordisk, MSD, AstraZeneca, ELPEN Pharma, Boehringer Ingelheim, Galenica Pharma, Epsilon Health and Winmedica. J.N.H. holds equity in Camp4 Therapeutics. A.E.L. is currently employed by and holds stock in Regeneron Pharmaceuticals, Inc. G.R.A. is an employee of Regeneron Pharmaceuticals and owns stock and stock options in Regeneron Pharmaceuticals. A.Pa. is currently employed by and holds stock in Regeneron Pharmaceuticals. O.G. is an employee and stock owner of UCB Pharma; this work was conducted before employment by UCB. N.G. is currently employed at Novo Nordisk A/S. M.E.K. is employed by SYNLAB Holding Deutschland GmbH. W.M. reports grants and personal fees from AMGEN, BASF, Sanofi, Siemens Diagnostics, Aegerion Pharmaceuticals, AstraZeneca, Danone Research, Numares, Pfizer and Hoffmann-La Roche; personal fees from MSD and Alexion; and grants from Abbott Diagnostics, all outside the submitted work. W.M. is employed by Synlab Holding Deutschland GmbH. C.J.O. is a current employee of Novartis Biomedical Research. S.M.D. receives research support from RenalytixAI and in-kind research support from Novo Nordisk, outside the scope of the current research. Ca.S. is currently employed by and holds stock in Regeneron Pharmaceuticals. J.C.F. received speaking honoraria from AstraZeneca, Merck and Novo Nordisk for talks over which he had full control of content and a consulting honorarium from AstraZeneca. H.L.L. receives support from a consulting contract between Data Tecnica International and the National Institute on Aging (NIA), National Institutes of Health (NIH). M.A.N. receives support from a consulting contract between Data Tecnica and the NIA, NIH. T.D.S. is a co-founder and shareholder of ZOE, Ltd. P.R.H.J.T. is a salaried employee of BioAge Labs, Inc. A.I.d.H. is currently an employee of AbbVie. The remaining authors declare no competing interests. Additional information Extended data is available for this paper at https://doi.org/10.1038/s41591-025-03827-z. Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41591-025-03827-z. Correspondence and requests for materials should be addressed to Ruth J. F. Loos. Peer review information Nature Medicine thanks Adam Gordon, Iftikar Kullo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: Anna Maria Ranzoni and Sonia Muliyil, in collaboration with the Nature Medicine team. Reprints and permissions information is available at www.nature.com/reprints. Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z Extended Data Fig. 1 | Distribution of obesity categories and average BMI in adult tuning and validation populations. Distribution of obesity categories and mean BMI (+/- standard deviation) across adult tuning and validation populations. Asian-specific BMI cutoffs (see Methods) were applied to East Asian (EAS), South Asian (SAS), and non-Hispanic Asian (AS) populations, in contrast to African (AFR), American (AMR), European (EUR), and Middle Eastern (MID) populations. UKBB, UK Biobank; MVP, the Million Veteran Program; GPC-UGR, the Uganda General Population Cohort. Sample sizes (distinct individuals), from left to right, for Tuning: 6154, 971, 1553, 2660, 8005, 20000; Validation: 12263, 2332, 18701, 10281, 8096, 4201, 1359, 1177, 13673, 69828, 340224; and BMI: 12263, 10281, 1359, 1177, 13673, 2332, 18701, 8096, 4201, 69828, 6154, 971, 1553, 2660, 8005, 340224. Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z Extended Data Fig. 2 | Prevalence of obesity categories across 1%-groups of PGSs. Prevalence of obesity category, with 95% confidence intervals based on the normal approximation to the binomial distribution, across 1%-groups of PGSKhera and PGSLC within the validation subset of the UKBB participants of European ancestry (N ~ 340k). The black dotted line denotes the average prevalence in the entire subset. The red and blue lines correspond to the prevalence of the obesity category within the top and bottom 1% of PGSKhera and PGSLC, respectively. Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z Extended Data Fig. 3 | Odds ratio per standard deviation (SD) increase of PGSLC for prevalent obesity categories. All PGS were standardised using the mean and SD of the PGS of individuals who did not have the outcome of interest (that is, those with a BMI value below the threshold for a given obesity category), to account for differences in prevalence across validation populations. MVP, Million Veteran Program; GPC-UGR, Uganda General Population Cohort; UKB, UK Biobank. Sample sizes (distinct individuals) per grouped set of estimates, left to right: AFR 12263, 2332, 18701; AMR 10281, 8096; AS 4201; EAS 1359; SAS 1177; EUR 13673, 69828, 340224. Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z Extended Data Fig. 4 | Distributional shifts of ancestry-specific scores before and after ancestry-calibration. Distributional shifts of ancestry-specific scores which are linearly combined to create PGSLC, across UK Biobank-tuning and BioMe-validation populations, before (top) and after (bottom) ancestry– calibration using 1000 Genomes reference data (Methods). Each plot shows a single ancestry-specific score, with separate lines showing the distribution across ancestries. For these plots, each score was standardised to mean zero and variance one once across all participants of a given study. Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z Extended Data Fig. 5 | Association between PGSLC and height trajectory between birth and age 24. Estimated using linear spline multilevel models with repeated measures from the ALSPAC cohort. Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z Extended Data Fig. 6 | AUC for obesity outcomes at age 50, stratified by sex and overweight/obesity status at age 20. Estimated in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Restricted to estimates where the number of individuals with the obesity outcome was at least 50. Population labels as provided by PLCO. Nature Medicine Article https://doi.org/10.1038/s41591-025-03827-z Extended Data Fig. 7 | Distribution of PGS across intensive lifestyle intervention trial arms. Scores were standardised to mean zero and variance one by population group, ignoring assigned trial arm. Vertical lines indicate the mean PGS per arm.