Whole-genome risk prediction of common diseases in human preimplantation embryos.
Whole-genome risk prediction of common diseases in human preimplantation embryos.
复制标题
DOI：
10.1038/s41591-022-01735-0
复制
发表时间：
2022-03
期刊：
影响因子：
82.9
通讯作者：
Rabinowitz M
中科院分区：
文献类型：
--
作者：
Kumar A;Im K;Banjevic M;Ng PC;Tunstall T;Garcia G;Galhardo L;Sun J;Schaedel ON;Levy B;Hongo D;Kijacic D;Kiehl M;Tran ND;Klatsky PC;Rabinowitz M
体外受精胚胎的植入前遗传检测(PGT)已被提出作为一种减少常见疾病传播的方法；然而，结合常见变异和罕见变异的影响的更全面的胚胎遗传学评估仍然是可用的。在这里，我们使用分子和统计技术的组合来可靠地推断110个胚胎的遗传基因组序列，并对12种常见疾病的易感性进行建模。我们观察到，在第5天胚胎活检病例中，与多基因风险评分相关的位点的基因型准确率为99.0-99.4%，而在第3天胚胎活检病例中，与多基因风险评分相关的位点的基因型准确率为97.2-99.1%。将罕见变异与多基因风险评分(PRS)相结合，放大了兄弟姐妹胚胎之间的预测差异。例如，在一对带有致病BRCA1变异的夫妇中，我们预测当联合使用时，兄弟姐妹之间的优势比(OR)会相差15倍，而单独使用BRCA1或PR则会产生4.5倍或3倍的差别。我们的发现可能为基于基因组的PGT在临床实践中的应用和实施提供参考。结合双亲基因组全基因组测序和植入前胚胎基因分型的计算方法可以准确预测胚胎的遗传基因组并计算多基因风险分数。
Preimplantation genetic testing (PGT) of in-vitro-fertilized embryos has been proposed as a method to reduce transmission of common disease; however, more comprehensive embryo genetic assessment, combining the effects of common variants and rare variants, remains unavailable. Here, we used a combination of molecular and statistical techniques to reliably infer inherited genome sequence in 110 embryos and model susceptibility across 12 common conditions. We observed a genotype accuracy of 99.0–99.4% at sites relevant to polygenic risk scoring in cases from day-5 embryo biopsies and 97.2–99.1% in cases from day-3 embryo biopsies. Combining rare variants with polygenic risk score (PRS) magnifies predicted differences across sibling embryos. For example, in a couple with a pathogenic BRCA1 variant, we predicted a 15-fold difference in odds ratio (OR) across siblings when combining versus a 4.5-fold or 3-fold difference with BRCA1 or PRS alone. Our findings may inform the discussion of utility and implementation of genome-based PGT in clinical practice. A computational approach combining whole-genome sequencing of parental genomes and genotyping of preimplantation embryos allows accurate prediction of the inherited genomes of embryos and calculation of polygenic risk scores.