Trans-ethnic Polygenic Risk Scores for Body Mass Index: An International Hundred K+ Cohorts Consortium Study

Abstract

Background While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans-ethnic PRS for body mass index (BMI) through this relatively new international effort. Methods The PRS model was developed trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta-analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis. Results We show that in the absence of a well powered trans-ethnic GWAS from which to derive SNPs and effect estimates, trans-ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred to adjust the summary statistics using trans-ethnic linkage disequilibrium reference panels. The ported trans-ethnic scores outperform population specific-PRS across all non-European ancestry populations investigated including East Asians and three-way admixed Brazilian cohort. Conclusions Widespread use of PRS in the clinic is hampered by a lack of genotyping data in individuals of non-European ancestry for the vast majority of traits. Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans-ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three-way admixed Brazilians.

Trans‐ethnic polygenic risk scores for body mass index

“…Our data showed that the TE PRS outperformed the ancestry‐specific models in the Chinese and Brazilian populations, whereas there is no appreciable loss in predictive power in European ancestry individuals when using a TE score. However, as shown in our study, the TE PRS for BMI has a poor performance in the admixed Brazilian population, although it outperforms the European PRS 42 . Increased genetic diversity and unique genetic drift and selection pressures contribute different LD patterns.…”

“…Currently, the performance of PRS for BMI prediction is relatively modest. Our recent PRS model for extreme BMI, that is, the top 1% and 5% has a moderate AUC of 0.703–0.736 with an acceptable predictive power in two large European populations, the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII) 42 . As further research and advancements continue, the BMI‐PRS model is expected to evolve and enhance its predictive power, ultimately contributing to more effective obesity prevention and treatment strategies.…”

“…The PRS for BMI was facilitated by the comprehensive identification of SNPs associated with BMI by the previous large‐scale GWAS by the GIANT consortium 34 . The GWAS meta‐analysis by the GIANT consortium, including 339 224 individuals of European ancestry, 34 was the basis of our PRS model 42 . The updated GWAS by the GIANT consortium and the UK Biobank included approximately 700 000 individuals of European ancestry 35 .…”

Transferability of polygenic risk score among diverse ancestries

“…Most recently, Qu et al 5 . addressed this limitation in the application of PRS for body mass index (BMI) in non‐European populations.…”