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

eLife

Daniel Backenroth¹  Shai Carmi¹  Einat Granot-Hershkovitz¹  Adam Green¹  Omer Weissbrod²  Kyle Gettler³  Judy H Cho⁴  Or Zuk⁵  Todd Lencz⁶ 

[1] Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel;Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, United States;Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States;Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States;The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, United States;Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States;Department of Statistics and Data Science, The Hebrew University of Jerusalem, Jerusalem, Israel;Departments of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, United States;Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of Northwell Health, Glen Oaks, United States;Institute for Behavioral Science, The Feinstein Institutes for Medical Research, Manhasset, United States;

关键词: polygenic risk scores;    embryo;    preimplantation genetic testing;    in vitro fertilization;    Human;   

DOI  :  10.7554/eLife.64716

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY