ESHRE supports the position of ESHG on embryo selection based on polygenic risk scores

ESHRE shares the concerns expressed by the European Society of Human Genetics (ESHG) over the use of polygenic risk scores in preimplantation genetic testing. A statement issued by the ESHG at the end of 2021 was firm in its objections that the use of PRSs in clinical practice is unproven and unethical.(1,2)

While ESHRE acknowledges that PRSs can generate useful information at the population level by identifying at-risk groups, the prediction intervals are so wide that individual predictions are highly unreliable. Thus, while benefits might be demonstrated in the future for specific patient populations, ESHRE agrees that at present there are serious scientific and ethical concerns surrounding this technology and introduction in the clinic is highly undesirable.

ESHRE’s concerns, as also expressed by the ESHG, are fourfold:
* First, there are always limited embryos for genetic testing in an IVF cycle, so each one will have some heightened PRS for some characteristics or diseases. Thus, a meaningful risk reduction cannot be achieved by merely excluding embryos with very high PRSs. This is a fundamental difference from the rationale in genetic testing for monogenic diseases, in which only affected (or very high risk) embryos are de-selected to prevent a great and likely harm.
* Second, a sibling cohort of embryos evaluated by PRS will exhibit great overlap between a variety of small risk factors evident in a multitude of gene variants inherited from parental genes.
* Third, PRS are unable to include phenotypical or environmental information, which further excludes a reliable risk estimate for complex diseases.
* Fourth, interaction between the different genetic variants is poorly understood, so, for instance, embryo selection to protect against one disease may inadvertently increase risks for others.

It thus remains ESHRE’s view that in the setting of embryo selection, 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.

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