Quantifying factors that affect polygenic risk score performance across diverse ancestries and age groups for body mass index

Polygenic risk scores (PRS) have led to enthusiasm for precision medicine. However, it is well documented that PRS do not generalize across groups differing in ancestry or sample characteristics e.g., age. Quantifying performance of PRS across different groups of study participants, using genome-wide association study (GWAS) summary statistics from multiple ancestry groups and sample sizes, and using different linkage disequilibrium (LD) reference panels may clarify factors limiting PRS transferability. To evaluate these factors in the PRS generation process, we generated body mass index (BMI) PRS (PRSBMI) in the Electronic Medical Records and Genomics network (N=75,661). Analyses were conducted in two ancestry groups (European and African) and three age ranges (adult, teenagers, and children). For PRSBMI calculations, we evaluated five LD reference panels and three GWAS summary statistics of varying sample size and ancestry. PRSBMI performance increased for both African and European ancestry individuals using cross-ancestry GWAS summary statistics compared to European-only summary statistics (6.3% and 3.7% relative R2 increase, respectively, pAfrican=0.038, pEuropean=6.26x10-4). The effects of LD reference panels were more pronounced in African ancestry study datasets. PRSBMI performance degraded in children; R2 was less than half of teenagers or adults. The effect of GWAS summary statistics sample size was small when modeled with the other factors. We also explored clinical comorbidities associated with the PRSBMI and identified associations with type 2 diabetes and coronary atherosclerosis. This study quantifies effects that ancestry, GWAS summary statistic sample size, and LD reference panel have on PRS performance, especially in cross-ancestry and age-specific analyses.