Generalizing polygenic risk scores from Europeans to Hispanics/Latinos.
paper
Cited
Public
- Authors
- Grinde, Kelsey E; Qi, Qibin; Thornton, Timothy A; Liu, Simin; Shadyab, Aladdin H; Chan, Kei Hang K; Reiner, Alexander P; Sofer, Tamar
- Year
- 2019
- Journal
- Genetic epidemiology
- PMID
- 30368908
- DOI
- 10.1002/gepi.22166
- PMCID
- PMC6330129
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. AlthoughΒ 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.
Observed SNPs gt1, gt2 likely have different LDs Ο with the unobserved causal SNP g in ancestral populations P1 and P2, leading to distinct tag SNPs in the two populations: gt1 in P1 and gt2 in P2. In the admixed population (ADM), the associations between the observed tag SNPs and the unobserved causal SNP depend on a, the proportion of admixed haplotypes that inherited this region from ancestral population P1.
The smoothed distribution of median root mean squared prediction errors (RMSPEs), where each median was computed over 500 repetitions of the same simulation setting, and the distribution is across all possible choices of causal SNP(s) in the locus. The left panel corresponds to the scenario in which there is a a single causal SNP in the locus, which is monomorphic in the African population, and the right panel corresponds to the scenario in which there are two causal SNPs, one of which is monomorphic in EA. In these figures, the training datasets were EA and ADM12,0.2, while the test dataset was ADM5, 0.4. Dashed vertical lines correspond to median of the plotted distribution. In the right panel, the lines corresponding to EA and meta-analysis (META) weights overlap.
Variance explained by the highest performing EA-based PRS and highest performing PRS across all approaches, for all investigated traits, in WHI Hispanic Americans. The numbers on the bars represent the number of SNPs used in the PRS. Table 3 provides more details about the PRSs, including p-value or r-value threshold, weights used, etc.
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