Utility of polygenic embryo screening for disease depends on the selection strategy.
Utility of polygenic embryo screening for disease depends on the selection strategy.
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DOI：
10.7554/elife.64716
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发表时间：
2021-10-12
期刊：
影响因子：
7.7
通讯作者：
Carmi S
中科院分区：
文献类型：
--
作者：
Lencz T;Backenroth D;Granot-Hershkovitz E;Green A;Gettler K;Cho JH;Weissbrod O;Zuk O;Carmi S
自2019年以来，已提供多基因风险评分（PRS）来筛选体外受精胚胎对成人疾病的遗传易感性，尽管缺乏对预期结果的全面建模。在这里，我们预测，基于责任阈值模型，在多基因胚胎筛查单一疾病后，复杂疾病风险的预期降低。这种筛选的潜在效用的一个强有力的决定因素是选择策略，这是一个以前没有研究过的因素。当仅排除具有非常高的PRS的胚胎时，所实现的风险降低是最小的。相比之下，选择具有最低PRS的胚胎可以导致实质性的相对风险降低，只要有足够数量的存活胚胎。我们系统地研究了几个因素对筛查效用的影响，包括：PRS解释的方差、胚胎数量、疾病患病率、父母PRS和父母疾病状态。我们考虑相对和绝对风险降低，以及人口平均和每对夫妇的风险降低，并检查多效性效应的风险。最后，我们证实了我们的理论预测，通过模拟"虚拟"夫妇和后代的基础上真实的基因组精神分裂症和克罗恩病的病例对照研究。我们讨论了我们的模型的假设和局限性，以及潜在的新出现的伦理问题。
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.