Screening embryos for polygenic disease risk: a review of epidemiological, clinical, and ethical considerations

Abstract

Background: The genetic composition of embryos generated by in vitro fertilization (IVF) can be examined with preimplantation genetic testing (PGT). Until recently, PGT was limited to detecting single-gene, high-risk pathogenic variants, large structural variants, and aneuploidy. Recent advances have made genome-wide genotyping of IVF embryos feasible and affordable, raising the possibility of screening embryos for their risk of polygenic diseases such as breast cancer, hypertension, diabetes, or schizophrenia. Despite a heated debate around this new technology, called polygenic embryo screening (PES; also PGT-P), it is already available to IVF patients in some countries. Several articles have studied epidemiological, clinical, and ethical perspectives on PES; however, a comprehensive, principled review of this emerging field is missing.

Objective and rationale: This review has four main goals. First, given the interdisciplinary nature of PES studies, we aim to provide a self-contained educational background about PES to reproductive specialists interested in the subject. Second, we provide a comprehensive and critical review of arguments for and against the introduction of PES, crystallizing and prioritizing the key issues. We also cover the attitudes of IVF patients, clinicians, and the public towards PES. Third, we distinguish between possible future groups of PES patients, highlighting the benefits and harms pertaining to each group. Finally, our review, which is supported by ESHRE, is intended to aid healthcare professionals and policymakers in decision-making regarding whether to introduce PES in the clinic, and if so, how, and to whom.

Search methods: We searched for PubMed-indexed articles published between 1/1/2003 and 1/3/2024 using the terms 'polygenic embryo screening', 'polygenic preimplantation', and 'PGT-P'. We limited the review to primary research papers in English whose main focus was PES for medical conditions. We also included papers that did not appear in the search but were deemed relevant.

Outcomes: The main theoretical benefit of PES is a reduction in lifetime polygenic disease risk for children born after screening. The magnitude of the risk reduction has been predicted based on statistical modelling, simulations, and sibling pair analyses. Results based on all methods suggest that under the best-case scenario, large relative risk reductions are possible for one or more diseases. However, as these models abstract several practical limitations, the realized benefits may be smaller, particularly due to a limited number of embryos and unclear future accuracy of the risk estimates. PES may negatively impact patients and their future children, as well as society. The main personal harms are an unindicated IVF treatment, a possible reduction in IVF success rates, and patient confusion, incomplete counselling, and choice overload. The main possible societal harms include discarded embryos, an increasing demand for 'designer babies', overemphasis of the genetic determinants of disease, unequal access, and lower utility in people of non-European ancestries. Benefits and harms will vary across the main potential patient groups, comprising patients already requiring IVF, fertile people with a history of a severe polygenic disease, and fertile healthy people. In the United States, the attitudes of IVF patients and the public towards PES seem positive, while healthcare professionals are cautious, sceptical about clinical utility, and concerned about patient counselling.

Wider implications: The theoretical potential of PES to reduce risk across multiple polygenic diseases requires further research into its benefits and harms. Given the large number of practical limitations and possible harms, particularly unnecessary IVF treatments and discarded viable embryos, PES should be offered only within a research context before further clarity is achieved regarding its balance of benefits and harms. The gap in attitudes between healthcare professionals and the public needs to be narrowed by expanding public and patient education and providing resources for informative and unbiased genetic counselling.

Keywords: PGT-P; clinical considerations; disease risk reduction; ethical considerations; polygenic embryo screening; polygenic risk scores; preimplantation genetic testing; statistical genetics.

The principles, estimated benefits, personal and societal harms, and clinical considerations of prioritizing IVF embryos based on their risk for late-onset, polygenic conditions.

Figure 1.

Polygenic risk scores and polygenic embryo screening. (A) Genetic testing for monogenic and polygenic diseases. For monogenic disorders (e.g. cystic fibrosis; left panel), the disease status is determined by the genotype in pathogenic variants of near-complete penetrance in the disease gene. Carriers of such variants can use PGT-M to avoid transmission to the next generation. For polygenic diseases, the risk is influenced by multiple variants throughout the genome, as well as by non-genetic factors. For some complex diseases (e.g. breast cancer; middle panel), high-penetrance variants in predisposition genes confer moderate to high risk to carriers, who can also use PGT-M to avoid transmission to future children. However, high-penetrance variants are rare, and the risk is otherwise determined by numerous common variants, each associated with a small increase or decrease in risk (right panel). The polygenic risk score (PRS) is the overall predicted risk based on the genotypes in all disease-associated common variants (here illustrated, for simplicity, as the difference between the number of risk and protective alleles). Individuals with high PRS will have higher-than-average risk, but will not necessarily become affected. (B) Polygenic embryo screening (PES). For each IVF embryo, DNA from a trophectoderm biopsy is sequenced/genotyped and PRSs are computed for one or more conditions. The risk profiles of the embryos are compared and a single embryo is prioritized for transfer according to a pre-determined criterion or ‘selection strategy’. In this illustration, under a strategy of prioritizing the embryo with the lowest average risk across conditions, embryo 1 would be prioritized. Alternative selection strategies may include exclusion of high-risk embryos and selection at random among the others or selection of the embryo with the lowest weighted average PRS. PES may also be performed only for informational purposes, using morphology or other factors for selection.

Figure 2.

A visual summary of the potential benefits of polygenic embryo screening along with practical limitations that will make risk reductions smaller. PRS, polygenic risk score.

Figure 3.

Three approaches for predicting the risk reduction due to polygenic embryo screening. (A) Statistical modelling using the liability threshold model. In this model, a disease is assumed to have an underlying (normally distributed) continuous liability, representing the sum of genetic and non-genetic risk factors. Individuals are affected if their liability is above a threshold. The liabilities of sibling embryos can be modelled based on quantitative genetic theory, and the risk of an embryo selected based on its polygenic risk score (PRS) can be predicted. The risk reduction is defined as the difference in risk between children born without selection and children born after being selected based on one or more PRSs (diagram on the right). (B) Simulations based on real genomes. In this approach, the genomes of real (unrelated) individuals are randomly mated in silico. For each ‘virtual couple’, genomes of embryos are simulated based on Mendel’s laws and realistic recombination rates. A PRS is computed for each embryo and the risk of each embryo is predicted. The risk reduction is then computed as in (A). (C) Simulations based on sibling pairs. In this approach, pairs (or larger sets) of siblings are identified in large cohorts such as the UK Biobank. For each pair of siblings, one or more PRSs are computed, and a sibling is selected either at random or based on having a favourable PRS profile. Real health outcomes are then extracted from the biobank, and the risk reduction is computed as the difference in the proportion of affected siblings between selection based on PRS and random selection (diagram at the bottom right).

Figure 4.

The predicted risk reduction with polygenic embryo screening (PES). (A) The predicted relative risk reduction versus the number of embryos when selecting embryos based on their polygenic risk score (PRS) for a single disease. The figure is based on a statistical modelling approach (Lencz et al., 2021) (Fig. 3A). We assume that embryos from a single oocyte retrieval cycle were screened with a PRS for a single disease and that the embryo with the lowest PRS was selected for transfer and was born. For three representative diseases, the figure shows the predicted relative risk reduction versus the number of embryos. Risk reduction curves are shown for two values of PRS accuracy, corresponding to lower and upper bounds on the current performance of PRS-based risk prediction for these diseases. For additional technical details, see the caption of Fig. 5. (B) The predicted risk reduction when selecting an embryo based on PRSs for multiple diseases. The figure is adapted from a published paper (Treff et al., 2020a) and is based on the UK biobank sibling approach (Fig. 3C). For each sibling pair, one sibling is either selected at random (‘baseline’) or based on a weighted average of 11 PRSs (‘polygenic embryo screening’), as computed by a company offering the screen. For each disease, the figure shows the baseline risk (the proportion of randomly selected siblings who are affected) and the PES-based risk. The relative risk reduction is shown on top of each bar. The inset zooms in on the same data for the eight rightmost conditions depicted in the main panel (same order).

Figure 5.

Examples for the best-case-scenario expected risk reduction. The table (left) uses a modelling approach (Lencz et al., 2021), as implemented in the online risk reduction calculator (https://pgt-p-outcome-calculator.shinyapps.io/selectioncalc/). We assume that embryos from a single oocyte retrieval cycle were screened with a polygenic risk score (PRS) for a single disease and that the embryo with the lowest PRS was selected for transfer and was born. We present results for three diseases, whose prevalence is estimated as 0.5% for Crohn’s disease (GBD Inflammatory Bowel Disease Collaborators, 2020), 1% for schizophrenia (Perala et al., 2007), and 10% for type 2 diabetes (Centers for Disease Control and Prevention). The accuracy of the PRS, as measured by r² (the proportion of variance in liability explained by the PRS), was previously estimated at ≈6% for Crohn’s disease, ≈7% for schizophrenia (Lencz et al., 2021), and ≈9% for type 2 diabetes (Ge et al., 2022). We therefore show results for lower and upper bounds of r² = 5% and 10%, respectively. The absolute risk reduction is the difference in risk between selecting an embryo at random (equal to the disease prevalence) and selecting based on PRS: absolute_risk_reduction= disease_prevalence—risk_of_selected_embryo. The relative risk reduction is the absolute risk reduction as a proportion of the initial risk: absolute_risk_reduction/disease_prevalence. The number of couples that would need to be screened in order to prevent a single case is computed as 1/absolute_risk_reduction. The bars on the right demonstrate the risk reduction for two diseases, Crohn’s disease and type 2 diabetes, when selecting the embryo with the lowest PRS out of five and when the PRS accuracy is r² = 5%. For each disease, the upper bar demonstrates the risk of an embryo selected at random (equal to the population prevalence), while the lower bar shows the risk of a child born after PES.

Figure 6.

A visual summary of the possible harms to patients, future children and society due to PES.