The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS_common) with a rare variant PRS (PRS_rare) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m²), obesity (BMI ≥ 30 kg/m²), and extreme obesity (BMI ≥ 40 kg/m²). We built PRSs_common and PRSs_rare using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS_common explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS_rare explained 1.49%, and 2.97% and 3.68%, respectively. The PRS_rare was associated with an increased risk of obesity and extreme obesity (OR_obesity = 1.37 per SD_PRS, P_obesity = 1.7x10^-85; OR_{extremeobesity} = 1.55 per SD_PRS, P_{extremeobesity} = 3.8x10^-40), which was attenuated, after adjusting for PRS_common (OR_obesity = 1.08 per SD_PRS, P_obesity = 9.8x10^-6; OR_{extremeobesity}= 1.09 per SD_PRS, P_{extremeobesity} = 0.02). When PRS_rare and PRS_common are combined, the increase in explained variance attributed to PRS_rare was small (incremental Nagelkerke R² = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRS_rare to PRS_common provided little improvement to the prediction of obesity (PRS_rare AUC = 0.591; PRS_common AUC = 0.708; PRS_combined AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS_rare provides limited improvement over PRS_common in the prediction of obesity risk, based on these large populations.