RT Journal Article
SR Electronic
T1 Population differentiation of polygenic score predictions under stabilizing selection
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.09.10.459833
DO 10.1101/2021.09.10.459833
A1 Sivan Yair
A1 Graham Coop
YR 2021
UL http://biorxiv.org/content/early/2021/09/11/2021.09.10.459833.abstract
AB Given the many loci uncovered by genome-wide association studies (GWAS), polygenic scores have become central to the drive for genomic medicine and have spread into various areas including evolutionary studies of adaptation. While promising, these scores are fraught with issues of portability across populations, due to the mis-estimation of effect sizes and missing causal loci across populations not represented in large-scale GWAS. The poor portability of polygenic scores at first seems at odds with the view that much of common genetic variation is shared among populations (Lewontin, 1972). Here we investigate one potential cause of this discrepancy: phenotypic stabilizing selection drives the turnover of genetic variation shared between populations at causal loci. Somewhat counter-intuitively, while stabilizing selection to the same optimum phenotype leads to lower phenotypic differentiation among populations, it increases genetic differentiation at GWAS loci and reduces the portability of polygenic scores constructed for unrepresented populations. We also find that stabilizing selection can lead to potentially misleading signals of the differentiation of average polygenic scores among populations. We extend our baseline model to investigate the impact of pleiotropy, gene-by-environment interactions, and directional selection on polygenic score predictions. Our work emphasizes stabilizing selection as a null evolutionary model to understand patterns of allele frequency differentiation and its impact on polygenic score portability and differentiation.Competing Interest StatementThe authors have declared no competing interest.