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Utility of polygenic embryo screening for disease depends on the selection strategy

Polygenic risk scores (PRSs) have been offered since 2019 to screen in vitro fertilization embryos for genetic liability to adult diseases, despite a lack of comprehensive modeling of expected outcomes. Here we predict, based on the liability threshold model, the expected reduction in complex diseas...

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Autores principales: Lencz, Todd, Backenroth, Daniel, Granot-Hershkovitz, Einat, Green, Adam, Gettler, Kyle, Cho, Judy H, Weissbrod, Omer, Zuk, Or, Carmi, Shai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510582/
https://www.ncbi.nlm.nih.gov/pubmed/34635206
http://dx.doi.org/10.7554/eLife.64716
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author Lencz, Todd
Backenroth, Daniel
Granot-Hershkovitz, Einat
Green, Adam
Gettler, Kyle
Cho, Judy H
Weissbrod, Omer
Zuk, Or
Carmi, Shai
author_facet Lencz, Todd
Backenroth, Daniel
Granot-Hershkovitz, Einat
Green, Adam
Gettler, Kyle
Cho, Judy H
Weissbrod, Omer
Zuk, Or
Carmi, Shai
author_sort Lencz, Todd
collection PubMed
description Polygenic risk scores (PRSs) have been offered since 2019 to screen in vitro fertilization embryos for genetic liability to adult diseases, despite a lack of comprehensive modeling of expected outcomes. Here we predict, based on the liability threshold model, the expected reduction in complex disease risk following polygenic embryo screening for a single disease. A strong determinant of the potential utility of such screening is the selection strategy, a factor that has not been previously studied. When only embryos with a very high PRS are excluded, the achieved risk reduction is minimal. In contrast, selecting the embryo with the lowest PRS can lead to substantial relative risk reductions, given a sufficient number of viable embryos. We systematically examine the impact of several factors on the utility of screening, including: variance explained by the PRS, number of embryos, disease prevalence, parental PRSs, and parental disease status. We consider both relative and absolute risk reductions, as well as population-averaged and per-couple risk reductions, and also examine the risk of pleiotropic effects. Finally, we confirm our theoretical predictions by simulating ‘virtual’ couples and offspring based on real genomes from schizophrenia and Crohn’s disease case-control studies. We discuss the assumptions and limitations of our model, as well as the potential emerging ethical concerns.
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spelling pubmed-85105822021-10-13 Utility of polygenic embryo screening for disease depends on the selection strategy Lencz, Todd Backenroth, Daniel Granot-Hershkovitz, Einat Green, Adam Gettler, Kyle Cho, Judy H Weissbrod, Omer Zuk, Or Carmi, Shai eLife Genetics and Genomics Polygenic risk scores (PRSs) have been offered since 2019 to screen in vitro fertilization embryos for genetic liability to adult diseases, despite a lack of comprehensive modeling of expected outcomes. Here we predict, based on the liability threshold model, the expected reduction in complex disease risk following polygenic embryo screening for a single disease. A strong determinant of the potential utility of such screening is the selection strategy, a factor that has not been previously studied. When only embryos with a very high PRS are excluded, the achieved risk reduction is minimal. In contrast, selecting the embryo with the lowest PRS can lead to substantial relative risk reductions, given a sufficient number of viable embryos. We systematically examine the impact of several factors on the utility of screening, including: variance explained by the PRS, number of embryos, disease prevalence, parental PRSs, and parental disease status. We consider both relative and absolute risk reductions, as well as population-averaged and per-couple risk reductions, and also examine the risk of pleiotropic effects. Finally, we confirm our theoretical predictions by simulating ‘virtual’ couples and offspring based on real genomes from schizophrenia and Crohn’s disease case-control studies. We discuss the assumptions and limitations of our model, as well as the potential emerging ethical concerns. eLife Sciences Publications, Ltd 2021-10-12 /pmc/articles/PMC8510582/ /pubmed/34635206 http://dx.doi.org/10.7554/eLife.64716 Text en © 2021, Lencz et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Genetics and Genomics
Lencz, Todd
Backenroth, Daniel
Granot-Hershkovitz, Einat
Green, Adam
Gettler, Kyle
Cho, Judy H
Weissbrod, Omer
Zuk, Or
Carmi, Shai
Utility of polygenic embryo screening for disease depends on the selection strategy
title Utility of polygenic embryo screening for disease depends on the selection strategy
title_full Utility of polygenic embryo screening for disease depends on the selection strategy
title_fullStr Utility of polygenic embryo screening for disease depends on the selection strategy
title_full_unstemmed Utility of polygenic embryo screening for disease depends on the selection strategy
title_short Utility of polygenic embryo screening for disease depends on the selection strategy
title_sort utility of polygenic embryo screening for disease depends on the selection strategy
topic Genetics and Genomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510582/
https://www.ncbi.nlm.nih.gov/pubmed/34635206
http://dx.doi.org/10.7554/eLife.64716
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