Leveraging fine-scale population structure reveals conservation in genetic effect sizes between human populations across a range of human phenotypes

Abstract

An understanding of genetic differences between populations is essential for avoiding confounding in genome-wide association studies (GWAS) and understanding the evolution of human traits. Polygenic risk scores constructed in one group perform poorly in highly genetically-differentiated populations, for reasons which remain controversial. We developed a statistical ancestry inference pipeline able to decompose ancestry both within and between countries, and applied it to the UK Biobank data. This identifies fine-scale patterns of genetic relatedness not captured by standard and widely used principal components (PCs), and allows fine-scale population stratification correction that removes both false positive and false negative associations for traits with geographic correlations. We also develop and apply ANCHOR, an approach leveraging segments of distinct ancestries within individuals to estimate similarity in underlying causal effect sizes between groups, using an existing PGS. Applying ANCHOR to >8000 people of mixed African and European ancestry, we demonstrate that estimated causal effect sizes are highly similar across these ancestries for 26 of 29 quantitative molecular and bioRxiv preprint doi: https://doi.org/10.1101/2023.08.08.552281; this version posted August 9, 2023. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license. non-molecular phenotypes (mean correlation 0.98 +/- 0.08), providing evidence that geneenvironment and gene-gene interactions do not play major roles in the poor prediction of Europeanancestry PRS scores in African populations for these traits, contradicting previous findings. Instead our results provide optimism that shared causal mutations operate similarly in different groups, focussing the challenge of improving GWAS “portability” between groups on joint fine-mapping.