Embryo selection based on polygenic risk score denounced as ‘unproven, unethical’ practice – ESHRE

A new position paper from the European Society of Human Genetics has described the selection of embryos based on polygenic risk scores as unethical practice, insisting that patients must be properly informed on the limitations of PRS and its reliability for predicting genetically complex diseases. ESHRE shares these concerns.

In a statement, ESHRE has expressed its support for the ESHG position paper, agreeing that at present there are serious scientific and ethical concerns about PRS in embryo testing and that introduction in the clinic is highly undesirable.(3) ESHRE lists four reasons for its concerns over the reliability of PRS, while adding that, even in cases where some analytic validity of a correlation can be demonstrated, the clinical utility of PRS remains at this time low to non-existent and cannot be supported in clinical practice.

PRSs already dubbed PGT-P by some clinics - are estimates of an individuals susceptibility to a specific trait obtained by aggregating the effects of multiple (and potentially millions) of genetic variants associated with that specific trait into a single figure. Yet the ESHG report notes that such traits are highly complex, determined by a combination of genes and environmental factors, and beyond the calculation of any single score derived only from genome-wide association studies. When PRS assessments are provided as direct-to-consumer tests, warns the report, their evaluation of a patients risk may be dangerously incomplete and can lead to grave misunderstandings.

The report emphasises the distinction between embryo assessment based on PRS and that based on single gene or chromosome testing. In the latter cases PGT-M, PGT-SR - the ability of the test to predict the development of a target disease in any offspring is high. PRSs, however, are only able to capture parts of the relevant genetic component.

The ESHG report concludes that at present carrying out a PRS test for embryo selection would be premature at best, adding the critical caveat that resources would be better applied in understanding the complex interplay between PRSs for a range of conditions and the environment than in offering an inadequately evaluated test to our future children.

The ESHG report echoes many of the concerns expressed in a New England Journal of Medicine special report in July last year, which not only listed the many factors which lower the predictive value of PRS but identified too some of the clinics (all in the USA) actually offering embryo selection based on PRS.(4) One of the clinics mentioned appeared to be providing patients with a PRS for education, household income, cognitive ability, and subjective well-being as part of a research protocol.

The NEJM report listed a six-point set of recommendations for communication with patients on the expected gains which might arise from PRS embryo testing, all focused on the provision of risk estimates specific to phenotype and ancestry. The report also advised against exaggerating the benefits of screening additional embryos.

And as did the ESHG paper, the NEJM report concludes that unless and until PRS for embryo screening is more robustly regulated, companies and clinicians who insist on offering this unproved, societally risky service should channel any access to [PRS] through research protocols, at no cost to patient participants.

However, PRS remains a highly controversial subject and any lack of consensus was no better highlighted than in a keenly followed session at last years online annual meeting of ESHRE in which a moral philosopher making a case for PRS also conceded that any clinical applicability of PRS was still five to ten years away.(5) Nevertheless, as in the ESHRE and ESHG statements, the prevailing arguments against PRS were based on reliability and accuracy, with many objections from the virtual floor questioning just how accurate the prediction of an embryos putative health might be from a PRS calculated from a battery of SNPs and genome-wide association studies.

1. See https://www.eshg.org/index.php?id=910&tx_news_pi1%5Bnews%5D=35&tx_news_pi1%5Bcontroller%5D=News&tx_news_pi1%5Baction%5D=detail&cHash=1c5c9e18d572aec81caa0ab5f3fb4bff

2. Forzano F, Antonova O, Clarke A, et al. The use of polygenic risk scores in pre-implantation genetic testing: an unproven, unethical practice. Eur J Hum Genet 2021; doi.org/10.1038/s41431-021-01000-x

3. See /Europe/Position-statements/PRS

4. Turley P, Meyer MN, Wang N, et al. Problems with using polygenic scores to select embryos. N Engl J Med 2021; 385: 78-86. doi:10.1056/NEJMsr2105065

5. See https://www.focusonreproduction.eu/article/ESHRE-News-ESHRE-2021-polygenic-risk

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Embryo selection based on polygenic risk score denounced as 'unproven, unethical' practice - ESHRE