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Population differentiation of polygenic score predictions under stabilizing selection

Given the many small-effect loci uncovered by genome-wide association studies (GWAS), polygenic scores have become central to genomic medicine, and have found application in diverse settings including evolutionary studies of adaptation. Despite their promise, polygenic scores have been found to suff...

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Detalles Bibliográficos
Autores principales: Yair, Sivan, Coop, Graham
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014188/
https://www.ncbi.nlm.nih.gov/pubmed/35430887
http://dx.doi.org/10.1098/rstb.2020.0416
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author Yair, Sivan
Coop, Graham
author_facet Yair, Sivan
Coop, Graham
author_sort Yair, Sivan
collection PubMed
description Given the many small-effect loci uncovered by genome-wide association studies (GWAS), polygenic scores have become central to genomic medicine, and have found application in diverse settings including evolutionary studies of adaptation. Despite their promise, polygenic scores have been found to suffer from limited portability across human populations. This at first seems in conflict with the observation that most common genetic variation is shared among populations. We investigate one potential cause of this discrepancy: stabilizing selection on complex traits. Counterintuitively, while stabilizing selection constrains phenotypic evolution, it accelerates the loss and fixation of alleles underlying trait variation within populations (GWAS loci). Thus even when populations share an optimum phenotype, stabilizing selection erodes the variance contributed by their shared GWAS loci, such that predictions from GWAS in one population explain less of the phenotypic variation in another. We develop theory to quantify how stabilizing selection is expected to reduce the prediction accuracy of polygenic scores in populations not represented in GWAS samples. In addition, we find that polygenic scores can substantially overstate average genetic differences of phenotypes among populations. We emphasize stabilizing selection around a common optimum as a useful null model to connect patterns of allele frequency and polygenic score differentiation. This article is part of the theme issue ‘Celebrating 50 years since Lewontin's apportionment of human diversity’.
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spelling pubmed-90141882022-04-19 Population differentiation of polygenic score predictions under stabilizing selection Yair, Sivan Coop, Graham Philos Trans R Soc Lond B Biol Sci Articles Given the many small-effect loci uncovered by genome-wide association studies (GWAS), polygenic scores have become central to genomic medicine, and have found application in diverse settings including evolutionary studies of adaptation. Despite their promise, polygenic scores have been found to suffer from limited portability across human populations. This at first seems in conflict with the observation that most common genetic variation is shared among populations. We investigate one potential cause of this discrepancy: stabilizing selection on complex traits. Counterintuitively, while stabilizing selection constrains phenotypic evolution, it accelerates the loss and fixation of alleles underlying trait variation within populations (GWAS loci). Thus even when populations share an optimum phenotype, stabilizing selection erodes the variance contributed by their shared GWAS loci, such that predictions from GWAS in one population explain less of the phenotypic variation in another. We develop theory to quantify how stabilizing selection is expected to reduce the prediction accuracy of polygenic scores in populations not represented in GWAS samples. In addition, we find that polygenic scores can substantially overstate average genetic differences of phenotypes among populations. We emphasize stabilizing selection around a common optimum as a useful null model to connect patterns of allele frequency and polygenic score differentiation. This article is part of the theme issue ‘Celebrating 50 years since Lewontin's apportionment of human diversity’. The Royal Society 2022-06-06 2022-04-18 /pmc/articles/PMC9014188/ /pubmed/35430887 http://dx.doi.org/10.1098/rstb.2020.0416 Text en © 2022 The Authors. https://creativecommons.org/licenses/by/4.0/Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, provided the original author and source are credited.
spellingShingle Articles
Yair, Sivan
Coop, Graham
Population differentiation of polygenic score predictions under stabilizing selection
title Population differentiation of polygenic score predictions under stabilizing selection
title_full Population differentiation of polygenic score predictions under stabilizing selection
title_fullStr Population differentiation of polygenic score predictions under stabilizing selection
title_full_unstemmed Population differentiation of polygenic score predictions under stabilizing selection
title_short Population differentiation of polygenic score predictions under stabilizing selection
title_sort population differentiation of polygenic score predictions under stabilizing selection
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014188/
https://www.ncbi.nlm.nih.gov/pubmed/35430887
http://dx.doi.org/10.1098/rstb.2020.0416
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