在一个基于人群的西班牙裔队列中，使用单祖先和多祖先模型评估阿尔茨海默病的多基因风险评分预测性能。

Evaluating polygenic risk score prediction performance for Alzheimer's disease in a population-based Hispanic cohort using single- and multi-ancestry models.

作者信息

Xu Yuexuan, Qiao Min, Gunasekaran Tamil I, Gu Yian, Reyes-Dumeyer Dolly, Piriz Angel, Sanchez Danurys, Soriano Belisa, Franco Yahaira, Coronado Zoraida Dominguez, Recio Patricia, Mejia Diones Rivera, Medrano Martin, Lantigua Rafael A, Honig Lawrence, Manly Jennifer J, Brickman Adam M, Vardarajan Badri N, Mayeux Richard

机构信息

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.

G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.

出版信息

Lancet Reg Health Am. 2025 Jul 25;49:101198. doi: 10.1016/j.lana.2025.101198. eCollection 2025 Sep.

DOI:10.1016/j.lana.2025.101198

PMID:40747112

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12312067/

Abstract

BACKGROUND

The Polygenic risk score (PRS) is effective in predicting Alzheimer's Disease (AD) risk among Europeans but remains understudied in Hispanics. Genome-wide association studies (GWAS) based on multiple ancestries can improve PRS prediction. We used GWAS data from the largest available African, European, and Hispanic populations and performed PRS analyses using novel methodologies to evaluate the performance of single- and multi-ancestry PRS models in predicting AD risk among Hispanic population.

METHODS

Prediction performance of Apolipoprotein-E (), single-ancestry PRS, and multi-ancestry PRS derived from GWAS-focused and method-focused approaches to clinical AD, incident AD, and cognition and were evaluated in 2961 Hispanic people from two large studies. The GWAS-focused approach constructs PRS based on multi-ancestry GWAS, while the method-focused approach uses novel multi-ancestry PRS methods, integrating GWAS summary statistics across ancestries. Ten repetitions of 5-fold cross-validation were used. In a subset, plasma biomarker data were used in a tuning-validation split to examine PRS performance in predicting single and combined biomarkers.

FINDINGS

The multi-ancestry PRS excluding , constructed using the method-focused approach, outperformed both single-ancestry and multi-ancestry PRSs from the GWAS-focused approach. The best method-focused PRS, incorporating summary statistics from GWASs of African, European, and Hispanic populations, explained up to 1.6%, 3.9%, and 1.7% of the variance in clinical AD, incident AD, and cognition, respectively-comparable to, or even higher than, the variance explained by the . Similar findings were observed in biomarker analyses. accounted for more variation in plasma P-tau levels and PRS explained more variation in Aβ levels.

INTERPRETATION

Integrating novel multi-ancestry PRS methods (e.g., PROSPER/PRS-CSx) with GWAS across ancestries enhances prediction accuracy for AD risk among Hispanic population. and PRS may point to different biological aspects of AD.

FUNDING

National Institutes of Health R01 AG072474, RF1 AG066107, 5R37AG015473, RF1AG015473, R56AG051876, R01 AG067501, and UL1TR001873.

摘要

背景

多基因风险评分（PRS）在预测欧洲人患阿尔茨海默病（AD）的风险方面有效，但在西班牙裔人群中仍研究不足。基于多个祖先群体的全基因组关联研究（GWAS）可以改善PRS预测。我们使用了来自最大规模的非洲、欧洲和西班牙裔人群的GWAS数据，并采用新方法进行PRS分析，以评估单祖先和多祖先PRS模型在预测西班牙裔人群AD风险方面的表现。

方法

在两项大型研究的2961名西班牙裔人群中，评估了载脂蛋白E（）、单祖先PRS以及源自聚焦GWAS和聚焦方法的方法用于临床AD、新发AD和认知的多祖先PRS的预测性能。聚焦GWAS的方法基于多祖先GWAS构建PRS，而聚焦方法的方法使用新的多祖先PRS方法，整合不同祖先群体的GWAS汇总统计数据。采用10次重复的5折交叉验证。在一个子集中，血浆生物标志物数据用于调整验证分割，以检验PRS在预测单一和组合生物标志物方面的性能。

结果

使用聚焦方法的方法构建的排除的多祖先PRS优于聚焦GWAS方法的单祖先和多祖先PRS。最佳的聚焦方法的PRS纳入了非洲、欧洲和西班牙裔人群GWAS的汇总统计数据，分别解释了临床AD、新发AD和认知中高达1.6%、3.9%和1.7%的变异——与解释的变异相当，甚至更高。在生物标志物分析中也观察到类似结果。解释了血浆P-tau水平中更多的变异，而PRS解释了Aβ水平中更多的变异。