In:
Frontiers in Endocrinology, Frontiers Media SA, Vol. 13 ( 2022-5-3)
Abstract:
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/m 2 ), obesity (BMI ≥ 30 kg/m 2 ), and extreme obesity (BMI ≥ 40 kg/m 2 ). 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 R 2 = 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.
Type of Medium:
Online Resource
ISSN:
1664-2392
DOI:
10.3389/fendo.2022.863893
DOI:
10.3389/fendo.2022.863893.s001
DOI:
10.3389/fendo.2022.863893.s002
DOI:
10.3389/fendo.2022.863893.s003
DOI:
10.3389/fendo.2022.863893.s004
DOI:
10.3389/fendo.2022.863893.s005
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2022
detail.hit.zdb_id:
2592084-4
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