Xiaoyang Li, Brisa S. Fernandes, Andi Liu, Jingchun Chen, Xiangning Chen, Zhongming Zhao, Yulin Dai
{"title":"GRPa‐PRS：一种识别多基因疾病遗传调控通路的风险分层方法","authors":"Xiaoyang Li, Brisa S. Fernandes, Andi Liu, Jingchun Chen, Xiangning Chen, Zhongming Zhao, Yulin Dai","doi":"10.1002/alz.70779","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>Polygenic risk score (PRS) assesses genetic risk for diseases, yet some high-risk individuals avoid illness while low-risk individuals develop it. We hypothesize that unknown counterfactors may reverse PRS predictions, offering insights into disease mechanisms and interventions.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>We developed a novel framework to identify genetically-regulated pathways (GRPas) using PRS-based stratification in Alzheimer's disease (AD) and schizophrenia (SCZ) cohorts. We calculated PRS models, stratified individuals by risk and diagnosis, and analyzed differential GRPas. For AD, analyses were further conducted with and without apolipoprotein E (<i>APOE)</i> effects, and across <i>APOE</i> haplotype.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>In AD, we identified several well-known AD-related pathways, including amyloid-beta clearance, tau protein binding, and resilience-related calcium signaling pathway, and divalent inorganic cation homeostasis.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>Our method offers flexibility for exploring GRPas among PRS-stratified subgroups using summary statistics or individual-level data. Fewer GRPas identified in the no-APOE AD model and SCZ suggest a more polygenic architecture, necessitating larger samples to detect significant GRPas.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Characterize genetically-regulated expression (GReX) among groups stratified by polygenic risk score (PRS)</li>\n \n <li>Leverage GReX and PRS to explore the resilience and susceptibility at the pathway level</li>\n \n <li>Highlight calcium signaling and cation homeostasis functions linked to resilience</li>\n \n <li>Enable personalized prevention by reinforcing the different resilience factors present or absent in each individual</li>\n \n <li>Our genetically-regulated pathway (GRPa) -PRS framework can be further expanded to other complex polygenic traits</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1000,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70779","citationCount":"0","resultStr":"{\"title\":\"GRPa-PRS: A risk stratification method to identify genetically-regulated pathways in polygenic diseases\",\"authors\":\"Xiaoyang Li, Brisa S. Fernandes, Andi Liu, Jingchun Chen, Xiangning Chen, Zhongming Zhao, Yulin Dai\",\"doi\":\"10.1002/alz.70779\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> INTRODUCTION</h3>\\n \\n <p>Polygenic risk score (PRS) assesses genetic risk for diseases, yet some high-risk individuals avoid illness while low-risk individuals develop it. We hypothesize that unknown counterfactors may reverse PRS predictions, offering insights into disease mechanisms and interventions.</p>\\n </section>\\n \\n <section>\\n \\n <h3> METHODS</h3>\\n \\n <p>We developed a novel framework to identify genetically-regulated pathways (GRPas) using PRS-based stratification in Alzheimer's disease (AD) and schizophrenia (SCZ) cohorts. We calculated PRS models, stratified individuals by risk and diagnosis, and analyzed differential GRPas. For AD, analyses were further conducted with and without apolipoprotein E (<i>APOE)</i> effects, and across <i>APOE</i> haplotype.</p>\\n </section>\\n \\n <section>\\n \\n <h3> RESULTS</h3>\\n \\n <p>In AD, we identified several well-known AD-related pathways, including amyloid-beta clearance, tau protein binding, and resilience-related calcium signaling pathway, and divalent inorganic cation homeostasis.</p>\\n </section>\\n \\n <section>\\n \\n <h3> DISCUSSION</h3>\\n \\n <p>Our method offers flexibility for exploring GRPas among PRS-stratified subgroups using summary statistics or individual-level data. Fewer GRPas identified in the no-APOE AD model and SCZ suggest a more polygenic architecture, necessitating larger samples to detect significant GRPas.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Highlights</h3>\\n \\n <div>\\n <ul>\\n \\n <li>Characterize genetically-regulated expression (GReX) among groups stratified by polygenic risk score (PRS)</li>\\n \\n <li>Leverage GReX and PRS to explore the resilience and susceptibility at the pathway level</li>\\n \\n <li>Highlight calcium signaling and cation homeostasis functions linked to resilience</li>\\n \\n <li>Enable personalized prevention by reinforcing the different resilience factors present or absent in each individual</li>\\n \\n <li>Our genetically-regulated pathway (GRPa) -PRS framework can be further expanded to other complex polygenic traits</li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":7471,\"journal\":{\"name\":\"Alzheimer's & Dementia\",\"volume\":\"21 10\",\"pages\":\"\"},\"PeriodicalIF\":11.1000,\"publicationDate\":\"2025-10-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70779\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Alzheimer's & Dementia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.70779\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer's & Dementia","FirstCategoryId":"3","ListUrlMain":"https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.70779","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
GRPa-PRS: A risk stratification method to identify genetically-regulated pathways in polygenic diseases
INTRODUCTION
Polygenic risk score (PRS) assesses genetic risk for diseases, yet some high-risk individuals avoid illness while low-risk individuals develop it. We hypothesize that unknown counterfactors may reverse PRS predictions, offering insights into disease mechanisms and interventions.
METHODS
We developed a novel framework to identify genetically-regulated pathways (GRPas) using PRS-based stratification in Alzheimer's disease (AD) and schizophrenia (SCZ) cohorts. We calculated PRS models, stratified individuals by risk and diagnosis, and analyzed differential GRPas. For AD, analyses were further conducted with and without apolipoprotein E (APOE) effects, and across APOE haplotype.
RESULTS
In AD, we identified several well-known AD-related pathways, including amyloid-beta clearance, tau protein binding, and resilience-related calcium signaling pathway, and divalent inorganic cation homeostasis.
DISCUSSION
Our method offers flexibility for exploring GRPas among PRS-stratified subgroups using summary statistics or individual-level data. Fewer GRPas identified in the no-APOE AD model and SCZ suggest a more polygenic architecture, necessitating larger samples to detect significant GRPas.
Highlights
Characterize genetically-regulated expression (GReX) among groups stratified by polygenic risk score (PRS)
Leverage GReX and PRS to explore the resilience and susceptibility at the pathway level
Highlight calcium signaling and cation homeostasis functions linked to resilience
Enable personalized prevention by reinforcing the different resilience factors present or absent in each individual
Our genetically-regulated pathway (GRPa) -PRS framework can be further expanded to other complex polygenic traits
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
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