Within- and Between-Family Validation of Nine Polygenic Risk Scores Developed in 1.5 Million Individuals: Implications for IVF, Embryo Selection, and Reduction in Lifetime Disease Risk

Abstract

Polygenic risk scores (PRSs) can reduce lifetime disease risk by guiding embryo selection during in vitro fertilization (IVF). We performed genome-wide association meta-analyses totaling [~]1.5 million individuals to construct state-of-the-art PRSs for nine diseases: Alzheimers disease, breast cancer, coronary artery disease, endometriosis, hypertension, prostate cancer, rheumatoid arthritis, type 1 diabetes, and type 2 diabetes. The resulting predictors achieved liability-scale R2 values of up to 22.9% for type 2 diabetes, matching or exceeding previously published benchmarks across all scores. Three PRS - Alzheimers disease, prostate cancer, and type 2 diabetes - explained over 75% of the common-SNP heritability. Within-family validation in 40,872 siblings across 18,840 families showed that, for eight of nine diseases, predictive performance was comparable to population-level results, confirming substantial direct genetic effects. Modeling of embryo selection suggests that couples with five euploid embryos could achieve 27-67% relative risk reduction across diseases. While the limitations of genetic data availability meant that these estimates were performed in European ancestry samples, we performed validation in the multi-ancestry US-based All of Us Biobank, demonstrating significant statistical power across ancestries. These findings support the clinical applicability of PRS-guided embryo selection to reduce the burden of common diseases.