Genetic risk scores (GRSs) are weighted sums of risk allele counts of single nucleotide polymorphisms (SNPs) associated with a disease or trait. Construction of GRSs is typically based on published results from Genome-Wide Association Studies (GWASs), the majority of which have been performed in large populations of European ancestry (EA) individuals. While many genotype-trait associations have been shown to generalize from EA populations to other populations, such as Hispanics/Latinos, the optimal choice of SNPs and weights for GRSs may differ between populations due to different linkage disequilibrium (LD) and allele frequency patterns. This is further complicated by the fact that different Hispanic/Latino populations may have different admixture patterns, so that LD and allele frequency patterns may not be the same among non-EA populations. Here, we compare various approaches for GRS 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, n=12,803). We consider multiple ways to select SNPs from association regions and to calculate the SNP weights. We study the performance of the resulting GRSs in an independent study of Hispanics/Latinos from the Woman Health Initiative (WHI, n=3,582). 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, as long as SNP weights are calculated using Hispanics/Latinos GWASs, or using the meta-analysis of EA and Hispanics/Latinos GWASs. The optimal approach depends on the genetic architecture of the trait.
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