Grinde Kelsey E, Qi Qibin, Thornton Timothy A, Liu Simin, Shadyab Aladdin H, Chan Kei Hang K, Reiner Alexander P, Sofer Tamar
Department of Biostatistics, University of Washington, Seattle, Washington.
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.
Genet Epidemiol. 2019 Feb;43(1):50-62. doi: 10.1002/gepi.22166. Epub 2018 Oct 15.
Polygenic risk scores (PRSs) are weighted sums of risk allele counts of single-nucleotide polymorphisms (SNPs) associated with a disease or trait. PRSs are typically constructed based on published results from Genome-Wide Association Studies (GWASs), and the majority of which has been performed in large populations of European ancestry (EA) individuals. Although many genotype-trait associations have generalized across populations, the optimal choice of SNPs and weights for PRSs may differ between populations due to different linkage disequilibrium (LD) and allele frequency patterns. We compare various approaches for PRS construction, using GWAS results from both large EA studies and a smaller study in Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL, ). We consider multiple approaches for selecting SNPs and for computing SNP weights. We study the performance of the resulting PRSs in an independent study of Hispanics/Latinos from the Women's Health Initiative (WHI, ). We support our investigation with simulation studies of potential genetic architectures in a single locus. We observed that selecting variants based on EA GWASs generally performs well, except for blood pressure trait. However, the use of EA GWASs for weight estimation was suboptimal. Using non-EA GWAS results to estimate weights improved results.
多基因风险评分（PRSs）是与疾病或性状相关的单核苷酸多态性（SNPs）风险等位基因计数的加权总和。PRSs通常基于全基因组关联研究（GWASs）的已发表结果构建，其中大部分研究是在欧洲血统（EA）个体的大群体中进行的。尽管许多基因型-性状关联在不同人群中具有普遍性，但由于连锁不平衡（LD）和等位基因频率模式不同，PRSs的SNP和权重的最佳选择在不同人群之间可能存在差异。我们使用来自大型欧洲裔研究以及一项针对西班牙裔/拉丁裔的较小研究（西班牙裔社区健康研究/拉丁裔研究，即HCHS/SOL）的GWAS结果，比较了构建PRSs的各种方法。我们考虑了多种选择SNP和计算SNP权重的方法。我们在一项来自妇女健康倡议（WHI）的针对西班牙裔/拉丁裔的独立研究中，研究了所得PRSs的性能。我们通过对单个基因座潜在遗传结构的模拟研究来支持我们的调查。我们观察到，基于欧洲裔GWASs选择变异通常表现良好，但血压性状除外。然而，使用欧洲裔GWASs进行权重估计并不理想。使用非欧洲裔GWAS结果来估计权重可改善结果。
