Luciana B Vargas, Mariah C Meyer, Iain R Konigsberg, Aastha Kakar, Patrick M Carry, Yun Li, Alana C Jones, Hemant K Tiwari, Vinodh Srinivasasainagendra, Nicole D Armstrong, Eimear E Kenny, Bogdan Pasaniuc, Marguerite R Irvin, Michael H Cho, Maggie A Stanislawski, Sridharan Raghavan, Jonathan A Shortt, Leslie A Lange, Ethan M Lange
{"title":"多基因风险评分的祖先校准改善了非洲裔美国成年人的风险分层和效果估计。","authors":"Luciana B Vargas, Mariah C Meyer, Iain R Konigsberg, Aastha Kakar, Patrick M Carry, Yun Li, Alana C Jones, Hemant K Tiwari, Vinodh Srinivasasainagendra, Nicole D Armstrong, Eimear E Kenny, Bogdan Pasaniuc, Marguerite R Irvin, Michael H Cho, Maggie A Stanislawski, Sridharan Raghavan, Jonathan A Shortt, Leslie A Lange, Ethan M Lange","doi":"10.1101/2025.06.18.25329573","DOIUrl":null,"url":null,"abstract":"<p><p>Polygenic risk score (PRS) distributions vary across populations, complicating PRS risk assessment. We evaluated the impact of <i>post-hoc</i> PRS calibration according to individualized genetic ancestry estimates on PRS performance using two large multi-ethnic PRS for type 2 diabetes (T2D) (PRS <sub>T2D</sub> ) and height (PRS <sub>height</sub> ), in 8,841 African American (AA) individuals from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. We calibrated each participant's score as a function of estimated genetic similarity to the Yoruba (GSYRI) cohort in the 1000 Genomes Project. Uncalibrated PRSs were significantly skewed by GSYRI. After calibration, 33.6% of individuals in the top decile of PRS <sub>T2D</sub> were reclassified and performance in the top PRS <sub>T2D</sub> decile improved from an OR of 7.97 [6.31-10.13] to 10.77 [8.41- 13.91] when compared to the lowest decile. Similarly, 55.0% of individuals in the top PRS <sub>height</sub> decile were reclassified with GSYRI calibration. The calibrated PRS <sub>height</sub> showed higher correlation with height (from 0.24 to 0.32, <i>p</i> <10 <sup>-7</sup> ), and increased mean height in the top PRS <sub>height</sub> decile ( <i>p</i> =5.7×10 <sup>-5</sup> ) when compared to the uncalibrated PRS <sub>height</sub> . Lastly, we show that evaluating uncalibrated PRS while adjusting for GSYRI in regression models can lead to inflated and unstable effect size estimates for both the PRS and GSYRI.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204301/pdf/","citationCount":"0","resultStr":"{\"title\":\"Ancestry Calibration of Polygenic Risk Scores Improves Risk Stratification and Effect Estimation in African American Adults.\",\"authors\":\"Luciana B Vargas, Mariah C Meyer, Iain R Konigsberg, Aastha Kakar, Patrick M Carry, Yun Li, Alana C Jones, Hemant K Tiwari, Vinodh Srinivasasainagendra, Nicole D Armstrong, Eimear E Kenny, Bogdan Pasaniuc, Marguerite R Irvin, Michael H Cho, Maggie A Stanislawski, Sridharan Raghavan, Jonathan A Shortt, Leslie A Lange, Ethan M Lange\",\"doi\":\"10.1101/2025.06.18.25329573\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Polygenic risk score (PRS) distributions vary across populations, complicating PRS risk assessment. We evaluated the impact of <i>post-hoc</i> PRS calibration according to individualized genetic ancestry estimates on PRS performance using two large multi-ethnic PRS for type 2 diabetes (T2D) (PRS <sub>T2D</sub> ) and height (PRS <sub>height</sub> ), in 8,841 African American (AA) individuals from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. We calibrated each participant's score as a function of estimated genetic similarity to the Yoruba (GSYRI) cohort in the 1000 Genomes Project. Uncalibrated PRSs were significantly skewed by GSYRI. After calibration, 33.6% of individuals in the top decile of PRS <sub>T2D</sub> were reclassified and performance in the top PRS <sub>T2D</sub> decile improved from an OR of 7.97 [6.31-10.13] to 10.77 [8.41- 13.91] when compared to the lowest decile. Similarly, 55.0% of individuals in the top PRS <sub>height</sub> decile were reclassified with GSYRI calibration. The calibrated PRS <sub>height</sub> showed higher correlation with height (from 0.24 to 0.32, <i>p</i> <10 <sup>-7</sup> ), and increased mean height in the top PRS <sub>height</sub> decile ( <i>p</i> =5.7×10 <sup>-5</sup> ) when compared to the uncalibrated PRS <sub>height</sub> . Lastly, we show that evaluating uncalibrated PRS while adjusting for GSYRI in regression models can lead to inflated and unstable effect size estimates for both the PRS and GSYRI.</p>\",\"PeriodicalId\":94281,\"journal\":{\"name\":\"medRxiv : the preprint server for health sciences\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-06-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204301/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"medRxiv : the preprint server for health sciences\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2025.06.18.25329573\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"medRxiv : the preprint server for health sciences","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2025.06.18.25329573","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Ancestry Calibration of Polygenic Risk Scores Improves Risk Stratification and Effect Estimation in African American Adults.
Polygenic risk score (PRS) distributions vary across populations, complicating PRS risk assessment. We evaluated the impact of post-hoc PRS calibration according to individualized genetic ancestry estimates on PRS performance using two large multi-ethnic PRS for type 2 diabetes (T2D) (PRS T2D ) and height (PRS height ), in 8,841 African American (AA) individuals from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. We calibrated each participant's score as a function of estimated genetic similarity to the Yoruba (GSYRI) cohort in the 1000 Genomes Project. Uncalibrated PRSs were significantly skewed by GSYRI. After calibration, 33.6% of individuals in the top decile of PRS T2D were reclassified and performance in the top PRS T2D decile improved from an OR of 7.97 [6.31-10.13] to 10.77 [8.41- 13.91] when compared to the lowest decile. Similarly, 55.0% of individuals in the top PRS height decile were reclassified with GSYRI calibration. The calibrated PRS height showed higher correlation with height (from 0.24 to 0.32, p <10 -7 ), and increased mean height in the top PRS height decile ( p =5.7×10 -5 ) when compared to the uncalibrated PRS height . Lastly, we show that evaluating uncalibrated PRS while adjusting for GSYRI in regression models can lead to inflated and unstable effect size estimates for both the PRS and GSYRI.
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