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. Our main finding is that a strong determinant of the potential utility of such screening is the selection strategy, a factor that has not been previously studied. Specifically, 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. For example, a relative risk reduction of ~50% for schizophrenia can be achieved by selecting the embryo with the lowest PRS out of five viable embryos. We systematically examine the impact of several factors on the utility of screening, including the variance explained by the PRS, the number of embryos, the disease prevalence, the parental PRSs, and the parental disease status. When quantifying the utility, we consider both relative and absolute risk reductions, as well as population-averaged and per-couple risk reductions. We 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.

中文翻译：

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多基因胚胎疾病筛查的效用取决于选择策略

尽管缺乏对预期结果的综合建模，但自 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责任。在这里，我们根据责任阈值模型预测，在对单一疾病进行多基因胚胎筛查后，复杂疾病风险的预期降低。我们的主要发现是，这种筛选的潜在效用的一个重要决定因素是选择策略，这是以前没有研究过的一个因素。具体而言，当仅排除具有非常高 PRS 的胚胎时，实现的风险降低是最小的。相比之下，如果有足够数量的可行胚胎，选择具有最低 PRS 的胚胎可以显着降低相对风险。例如，通过从五个可存活胚胎中选择具有最低 PRS 的胚胎，可以将精神分裂症的相对风险降低约 50%。我们系统地检查了几个因素对筛查效用的影响，包括由 PRS 解释的方差、胚胎数量、疾病流行率、父母 PRS 和父母疾病状态。在量化效用时，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。我们还检查了多效性效应的风险。最后，我们通过基于精神分裂症和克罗恩病病例对照研究的真实基因组模拟“虚拟”夫妇和后代来确认我们的理论预测。我们讨论模型的假设和局限性，