The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations. Wang, Z., Choi, S. W., Chami, N., Boerwinkle, E., Fornage, M., Redline, S., Bis, J. C, Brody, J. A, Psaty, B. M, Kim, W., McDonald, M. N, Regan, E. A, Silverman, E. K, Liu, C., Vasan, R. S, Kalyani, R. R, Mathias, R. A, Yanek, L. R, Arnett, D. K, Justice, A. E, North, K. E, Kaplan, R., Heckbert, S. R, de Andrade, M., Guo, X., Lange, L. A, Rich, S. S, Rotter, J. I, Ellinor, P. T, Lubitz, S. A, Blangero, J., Shoemaker, M B., Darbar, D., Gladwin, M. T, Albert, C. M, Chasman, D. I, Jackson, R. D, Kooperberg, C., Reiner, A. P, O'Reilly, P. F, & Loos, R. J F Front Endocrinol (Lausanne), 13:863893, 2022.
The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations [link]Paper  doi  abstract   bibtex   
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 (PRScommon) with a rare variant PRS (PRSrare) 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 PRSscommon and PRSsrare 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 PRScommon 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 PRSrare explained 1.49%, and 2.97% and 3.68%, respectively. The PRSrare was associated with an increased risk of obesity and extreme obesity (ORobesity = 1.37 per SDPRS, Pobesity = 1.7x10-85; ORextremeobesity = 1.55 per SDPRS, Pextremeobesity = 3.8x10-40), which was attenuated, after adjusting for PRScommon (ORobesity = 1.08 per SDPRS, Pobesity = 9.8x10-6; ORextremeobesity= 1.09 per SDPRS, Pextremeobesity = 0.02). When PRSrare and PRScommon are combined, the increase in explained variance attributed to PRSrare was small (incremental Nagelkerke R2 = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRSrare to PRScommon provided little improvement to the prediction of obesity (PRSrare AUC = 0.591; PRScommon AUC = 0.708; PRScombined AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRSrare provides limited improvement over PRScommon in the prediction of obesity risk, based on these large populations.
@article{Wang:2022ab,
	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 (PRScommon) with a rare variant PRS (PRSrare) 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 PRSscommon and PRSsrare 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 PRScommon 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 PRSrare explained 1.49%, and 2.97% and 3.68%, respectively. The PRSrare was associated with an increased risk of obesity and extreme obesity (ORobesity = 1.37 per SDPRS, Pobesity = 1.7x10-85; ORextremeobesity = 1.55 per SDPRS, Pextremeobesity = 3.8x10-40), which was attenuated, after adjusting for PRScommon (ORobesity = 1.08 per SDPRS, Pobesity = 9.8x10-6; ORextremeobesity= 1.09 per SDPRS, Pextremeobesity = 0.02). When PRSrare and PRScommon are combined, the increase in explained variance attributed to PRSrare was small (incremental Nagelkerke R2 = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRSrare to PRScommon provided little improvement to the prediction of obesity (PRSrare AUC = 0.591; PRScommon AUC = 0.708; PRScombined AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRSrare provides limited improvement over PRScommon in the prediction of obesity risk, based on these large populations.},
	author = {Wang, Zhe and Choi, Shing Wan and Chami, Nathalie and Boerwinkle, Eric and Fornage, Myriam and Redline, Susan and Bis, Joshua C and Brody, Jennifer A and Psaty, Bruce M and Kim, Wonji and McDonald, Merry-Lynn N and Regan, Elizabeth A and Silverman, Edwin K and Liu, Ching-Ti and Vasan, Ramachandran S and Kalyani, Rita R and Mathias, Rasika A and Yanek, Lisa R and Arnett, Donna K and Justice, Anne E and North, Kari E and Kaplan, Robert and Heckbert, Susan R and de Andrade, Mariza and Guo, Xiuqing and Lange, Leslie A and Rich, Stephen S and Rotter, Jerome I and Ellinor, Patrick T and Lubitz, Steven A and Blangero, John and Shoemaker, M Benjamin and Darbar, Dawood and Gladwin, Mark T and Albert, Christine M and Chasman, Daniel I and Jackson, Rebecca D and Kooperberg, Charles and Reiner, Alexander P and O'Reilly, Paul F and Loos, Ruth J F},
	date-added = {2024-05-19 20:58:42 -0400},
	date-modified = {2024-05-19 20:58:42 -0400},
	doi = {10.3389/fendo.2022.863893},
	journal = {Front Endocrinol (Lausanne)},
	journal-full = {Frontiers in endocrinology},
	keywords = {BMI - body mass index; C+T; PRS-CS; burden score; lassosum; obesity risk; polygenic risk score; rare variants},
	mesh = {Gene Frequency; Genetic Variation; Genome-Wide Association Study; Humans; Obesity; Whole Genome Sequencing},
	pages = {863893},
	pmc = {PMC9110787},
	pmid = {35592775},
	url = {https://pubmed.ncbi.nlm.nih.gov/35592775/},
	pst = {epublish},
	title = {The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations},
	volume = {13},
	year = {2022},
	bdsk-url-1 = {https://doi.org/10.3389/fendo.2022.863893}}
Downloads: 0
About
Documentation
Keywords
Search
Users
Terms and Conditions of Use
Privacy Policy
Sitemap
© BibBase.org 2021