Preimplantation Genetic Testing for Polygenic Disease Relative Risk Reduction: Evaluation of Genomic Index Performance in 11,883 Adult Sibling Pairs

Abstract

Preimplantation genetic testing for polygenic disease risk (PGT-P) represents a new tool to aid in embryo selection. Previous studies demonstrated the ability to obtain necessary genotypes in the embryo with accuracy equivalent to in adults. When applied to select adult siblings with known type I diabetes status, a reduction in disease incidence of 45–72% compared to random selection was achieved. This study extends analysis to 11,883 sibling pairs to evaluate clinical utility of embryo selection with PGT-P. Results demonstrate simultaneous relative risk reduction of all diseases tested in parallel, which included diabetes, cancer, and heart disease, and indicate applicability beyond patients with a known family history of disease.

Screening embryos for polygenic conditions and traits: ethical considerations for an emerging technology

“…Polygenic embryo screening (PES) – the use of polygenic risk scores for complex phenotypes as a component of preimplantation genetic testing (PGT) – has emerged as a commercially available service, despite almost no public deliberation about its ethical, clinical, and societal implications 1 , 2 . By contrast, PGT has been used for many years to avoid implantation of embryos harboring aneuploidies (e.g., PGT-A) or pre-specified, monogenic disease-causing alleles (PGT-M), and a large literature has explored questions about meaningful informed consent, procreative autonomy, and equity issues, among many others 3 - 5 .…”

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

“…In future work, it will be interesting to model the case when one or more parents are affected or when the parents already have an affected child. Further, it is likely that parents would attempt to screen the embryos for more than one disease [23]. A related important question for future studies is to what extent selecting for a lower risk of one disease (or a set of diseases) would increase risk for diseases that were not included in the screen.…”

“…For example, we have recently demonstrated that screening embryos on the basis of polygenic scores for quantitative traits (such as height or intelligence) has limited predictive power in most realistic scenarios (Karavani et al, 2019), and that is a more significant determinant of PES utility for quantitative traits compared with the number of available embryos ( n ). On the other hand, a series of four studies (Lello et al, 2020; Treff, Eccles, et al, 2019; Treff et al, 2020; Treff, Zimmerman, et al, 2019) conducted by a private company providing embryo screening services has suggested that PES for dichotomous disease risk may have significant clinical utility. However, these studies examined a relatively limited range of scenarios, primarily focusing on distinctions between sibling pairs discordant for illness, and did not provide a comprehensive examination of the potential utility of PES.…”

“…In studies of potential clinical utility of PRSs in adults, attention has focused on those in the highest percentiles of risk, in which odds ratios become sufficiently large to be clinically meaningful (Chatterjee et al, 2016; Dai et al, 2019; Gibson, 2019; Khera et al, 2018; Mars et al, 2020; Mavaddat et al, 2019; Torkamani et al, 2018). To our knowledge, PES is currently being employed in a similar fashion, following a strategy of excluding embryos with extremely high (top 2-percentiles) PRS (Treff, Eccles, et al, 2019; Treff et al, 2020), which we term “ high-risk exclusion ” (HRE: Figure 1B , upper panel). In such a strategy, after high-risk embryos are set aside, an embryo is randomly selected for implantation among the remaining available embryos.…”

Embryo Genetics

“…The results of this study indicate that AMA couples who are also ADPKD patients have an increased risk of generating aneuploid embryos, but ADPKD-linked male infertility does not promote an increased aneuploidy rate. In a third article, the possibility of testing embryos not only for monogenic diseases, but also for polygenic conditions (PGT-P) is presented, with a strategy of disease relative risk reduction to evaluate the potential clinical utility of embryo selection with PGT-P [ 6 ]. The results demonstrate the potential for simultaneous relative risk reduction for all diseases tested in parallel, which include diabetes, cancer, and heart disease, and indicate applicability beyond patients with a known family history of disease.…”