Whole-genome risk prediction of common diseases in human preimplantation embryos
Akash Kumar, Kate Im, Milena Banjevic, Pauline C. Ng, Tate Tunstall, Geronimo Garcia, Luisa Galhardo, Jiayi Sun, Oren N. Schaedel, Brynn Levy, Donna Hongo, Dusan Kijacic, Michelle Kiehl, Nam D. Tran, Peter Klatsky, Matthew Rabinowitz
Abstract
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.