Please use this identifier to cite or link to this item:
https://hdl.handle.net/2445/222885
Title: | Pathway polygenic risk scores (pPRS) for the analysis of gene-environment interaction |
Author: | Gauderman, W. James Fu, YuHong Queme, Bryan Kawaguchi, Eric S. Wang, Yinqiao Morrison, John Brenner, Hermann Chan, Andrew Gruber, Stephen B. Keku, Temitope Li, Li Moreno Aguado, Víctor Pellatt, Andrew J. Peters, Ulrike Samadder, N. Jewel Schmit, Stephanie L. Ulrich, Cornelia M. Um, Caroline Wu, Anna Lewinger, Juan Pablo Drew, David A. Mi, Huaiyu |
Keywords: | Factors de risc en les malalties Agents antiinflamatoris Càncer colorectal Risk factors in diseases Antiinflammatory agents Colorectal cancer |
Issue Date: | 5-Aug-2025 |
Publisher: | Public Library of Science (PLoS) |
Abstract: | A polygenic risk score (PRS) is used to quantify the combined disease risk of many genetic variants. For complex human traits there is interest in determining whether the PRS modifies, i.e. interacts with, important environmental (E) risk factors. Detection of a PRS by environment (PRS x E) interaction may provide clues to underlying biology and can be useful in developing targeted prevention strategies for modifiable risk factors. The standard PRS may include a subset of variants that interact with E but a much larger subset of variants that affect disease without regard to E. This latter subset will dilute the underlying signal in former subset, leading to reduced power to detect PRS x E interaction. We explore the use of pathway-defined PRS (pPRS) scores, using state of the art tools to annotate subsets of variants to genomic pathways. We demonstrate via simulation that testing targeted pPRS x E interaction can yield substantially greater power than testing overall PRS x E interaction. We also analyze a large study (N = 78,253) of colorectal cancer (CRC) where E = non-steroidal anti-inflammatory drugs (NSAIDs), a well-established protective exposure. While no evidence of overall PRS x NSAIDs interaction (p = 0.41) is observed, a significant pPRS x NSAIDs interaction (p = 0.0003) is identified based on SNPs within the TGF-β/ gonadotropin releasing hormone receptor (GRHR) pathway. NSAIDS is protective (OR=0.84) for those at the 5th percentile of the TGF-β/GRHR pPRS (low genetic risk, OR), but significantly more protective (OR=0.70) for those at the 95th percentile (high genetic risk). From a biological perspective, this suggests that NSAIDs may act to reduce CRC risk specifically through genes in these pathways. From a population health perspective, our result suggests that focusing on genes within these pathways may be effective at identifying those for whom NSAIDs-based CRC-prevention efforts may be most effective. |
Note: | Reproducció del document publicat a: https://doi.org/10.1371/journal.pgen.1011543 |
It is part of: | PLoS Genetics, 2025, vol. 21, num.8 |
URI: | https://hdl.handle.net/2445/222885 |
Related resource: | https://doi.org/10.1371/journal.pgen.1011543 |
ISSN: | 1553-7390 |
Appears in Collections: | Articles publicats en revistes (Ciències Clíniques) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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