Ancestry Calibration of Polygenic Risk Scores Improves Risk Stratification and Effect Estimation in African American Adults.

medRxiv : the preprint server for health sciences Pub Date : 2025-06-18 DOI:10.1101/2025.06.18.25329573

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

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Abstract

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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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。

多基因风险评分（PRS）在不同人群中的分布不同，使PRS风险评估复杂化。我们评估了基于个性化遗传祖先估计的事后PRS校准对PRS性能的影响，使用2型糖尿病（T2D）（PRS T2D）和身高（PRS高度）的两个大型多种族PRS， 8841名来自中风地理和种族差异原因（REGARDS）研究的非裔美国人（AA）个体。我们将每个参与者的分数校准为与1000基因组计划中约鲁巴人（GSYRI）队列的估计遗传相似性的函数。未校准的PRSs被GSYRI显著偏斜。校正后，33.6%的前十分位数个体被重新分类，与最低十分位数相比，前十分位数的OR从7.97[6.31-10.13]提高到10.77[8.41- 13.91]。同样，55.0%的最高PRS高度十分位数的个体被GSYRI校准重新分类。校正后的PRS高度与高度有较高的相关性（从0.24到0.32,p -7），与未校正的PRS高度相比，最高PRS高度十分位数的平均高度增加（p =5.7×10 -5）。最后，我们表明，在评估未校准的PRS时，在回归模型中调整GSYRI会导致PRS和GSYRI的效应大小估计膨胀和不稳定。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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medRxiv : the preprint server for health sciences

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