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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