ArticlePLoS genetics2025
Pathway polygenic risk scores (pPRS) for the analysis of gene-environment interaction.
Article in PLoS genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Socioeconomic position, genetic susceptibility, and epigenetic profiles in obesity across the life course: a systematic review.International journal of obesity (2005) · 2026Pooled it
- Shaping the future of early-onset colorectal cancer prevention.Nature reviews. Cancer · 2026Review
- From genes to environment: A life-course approach to prevent pediatric autoimmune diseases.World journal of clinical pediatrics · 2026Review
- Partitioned blood pressure polygenic risk reveals differential genetic effects of tissue-specific enhancers and their interactions on cardiovascular disease.Research square · 2026Article
- TGF-β Pathway-Based Polygenic Risk Score Modifies the Association between Red Meat Intake and Colorectal Cancer Risk: Application of a Novel Pathway-Based PRS Method.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2026Article
- Dissecting the polygenic architecture of psychopathology via singular value decomposition of eight psychiatric genome-wide association studies and evaluation of component-based polygenic scores.General psychiatry · 2026Article
- ExposoGraph: An Interactive Platform for Carcinogen Bioactivation and Detoxification Pathway Visualization.Medical oncology (Northwood, London, England) · 2026Article
- SNPWay: streamlined SNP-to-function and pathway over-representation analysis.bioRxiv : the preprint server for biology · 2026Article
- From SNPs to pathways: a genome-wide benchmark of annotation discrepancies and their impact on protein- and pathway-level inference.BMC genomics · 2026Article
- ExposoGraph: An Interactive Platform for Carcinogen Bioactivation and Detoxification Pathway Visualization.Research square · 2026Article
- ExposoGraph: An Interactive Platform for Carcinogen Bioactivation and Detoxification Pathway Visualization.bioRxiv : the preprint server for biology · 2026Article
- From SNPs to Pathways: A genome-wide benchmark of annotation discrepancies and their impact on protein- and pathway-level inference.bioRxiv : the preprint server for biology · 2026Article
- Pathway-specific polygenic scores substantially increase the discovery of gene-adiposity interactions impacting liver biomarkers.HGG advances · 2026Article
- Methods for modeling gene-environment interplay using polygenic risk scores.Statistical applications in genetics and molecular biology · 2026Review
- Red meat intake interacts with a TGF-β-pathway-based polygenic risk score to impact colorectal cancer risk: Application of a novel approach for polygenic risk score construction.medRxiv : the preprint server for health sciences · 2025Article
- Pathway-specific polygenic scores substantially increase the discovery of gene-adiposity interactions impacting liver biomarkers.medRxiv : the preprint server for health sciences · 2025Article
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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.
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