Utility and First Clinical Application of Screening Embryos for Polygenic Disease Risk Reduction

Abstract

For over 2 decades preimplantation genetic testing (PGT) has been in clinical use to reduce the risk of miscarriage and genetic disease in patients with advanced maternal age and risk of transmitting disease. Recently developed methods of genome-wide genotyping and machine learning algorithms now offer the ability to genotype embryos for polygenic disease risk with accuracy equivalent to adults. In addition, contemporary studies on adults indicate the ability to predict polygenic disorders with risk equivalent to monogenic disorders. Existing biobanks provide opportunities to model the clinical utility of polygenic disease risk reduction among sibling adults. Here, we provide a mathematical model for the use of embryo screening to reduce the risk of type 1 diabetes. Results indicate a 45-72% reduced risk with blinded genetic selection of one sibling. The first clinical case of polygenic risk scoring in human preimplantation embryos from patients with a family history of complex disease is reported. In addition to these data, several common and accepted practices place PGT for polygenic disease risk in the applicable context of contemporary reproductive medicine. In addition, prediction of risk for PCOS, endometriosis, and aneuploidy are of particular interest and relevance to patients with infertility and represent an important focus of future research on polygenic risk scoring in embryos.

A systematic framework for assessing the clinical impact of polygenic risk scores

“…Polygenic risk scores are easy to produce, simple to understand, and in the literature they are currently the most prominent metric for reporting disease risk attributable to genetics 37 . Unfortunately, their utility is often either convoluted by additional covariates 6 , overstated due to overfitting 38,39 , poorly constructed due to simplistic selection of underlying SNPs 40,41 , or used in sensitive social issues 42,43 . This work aims to resolve these issues by providing a comprehensive yet straightforward analysis of polygenic risk score methods on a multitude of traits while providing extensive supplementary analyses.…”

PREIMPLANTATION GENETIC TESTING: Preimplantation genetic testing for polygenic disease risk

“…Four years following the first reported birth following PGT for a monogenic disease (Handyside et al 1992), Nobel Laureate Robert Edwards and his colleague Joseph Schulman proposed that 'many of the major human traits are highly polygenic, and that a large number of genes may possibly be analysed in embryos in the near future' (Schulman & Edwards 1996). However, only recently has this become a reality, as the first reported clinical application of PGT for polygenic disease risk (PGT-P) was published in 2019 (Treff et al 2019a), which includes analysis of multiple diseases (Fig. 2).…”

“…2). This capability required several major developments: first, the availability of population-level genome-wide data with corresponding clinical phenotypes; second, the ability to perform accurate genomic prediction of a complex (Handyside et al 1990); (B) the first PGT birth reported (Handyside et al 1992); (C) the first human whole genome sequence (WGS) published (Lander et al 2001); (D) the first genome-wide association study (GWAS) reported (Klein et al 2005); and (E) the first PGT for polygenic disease risk (PGT-P) reported (Treff et al 2019a).…”

“…Reproduction (2020) 160 A13-A17 human trait (Lello et al 2018); third, the capability to obtain embryonic genome-wide genotypes with accuracy equivalent to adults (Treff et al 2019b); and fourth, the capability to achieve significant reduction in polygenic disease risk following genetic selection of a sibling (Treff et al 2019a). The latter of these developments, demonstrating clinical utility in genetic selection across >2000 siblings, is an important outcome to highlight.…”

Utility of polygenic embryo screening for disease depends on the selection strategy

“…Another potential clinical application of PRSs is preimplantation screening of in vitro fertilization (IVF) embryos. Although currently in use (Treff, Eccles, et al, 2019) and fraught with ethical concerns (Lázaro-Muñoz et al, 2020), "polygenic embryo screening" (PES) has not yet received much research attention from either geneticists or ethicists. Understanding the statistical properties of PES forms a critical foundation to ethical consideration of the practice (Lázaro-Muñoz et al, 2020).…”