Variable prediction accuracy of polygenic scores within an ancestry group

Fields as diverse as human genetics and sociology are increasingly using polygenic scores based on genome-wide association studies (GWAS) for phenotypic prediction. However, recent work has shown that polygenic scores have limited portability across groups of different genetic ancestries, restricting the contexts in which they can be used reliably and potentially creating serious inequities in future clinical applications. Using the UK Biobank data, we demonstrate that even within a single ancestry group (i.e., when there are negligible differences in linkage disequilibrium or in causal alleles frequencies), the prediction accuracy of polygenic scores can depend on characteristics such as the socio-economic status, age or sex of the individuals in which the GWAS and the prediction were conducted, as well as on the GWAS design. Our findings highlight both the complexities of interpreting polygenic scores and underappreciated obstacles to their broad use.This repository contains summary statistics for all association tests (including GWAS and effect re-estimations for sets of pre-ascertained SNPs) that were performed in this study. The directory "gwas_by_sample_characteristics" stores data corresponding to Figures 1, 2, and Appendix-figures 1-5,13-15, and Appendix-table 2. The directory "standard_vs_sibling_gwas" stores data corresponding to Figure 3, and Appendix-figures 11, 12, 16. Additional README files can be found within each directory. Funding provided by: National Institute of General Medical SciencesCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000057Award Number: GM121372Funding provided by: National Human Genome Research InstituteCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000051Award Number: HG008140Funding provided by: Robert Wood Johnson FoundationCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000867Award Number: 84337817Funding provided by: Simons FoundationCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000893Award Number: 63331