The use of polygenic risk scores in pre-implantation genetic testing: an unproven, unethical practice

Polygenic risk score analyses on embryos (PGT-P) are being marketed by some private testing companies to parents using in vitro fertilisation as being useful in selecting the embryos that

carry the least risk of disease in later life. It appears that at least one child has been born after such a procedure. But the utility of a PRS in this respect is severely limited, and to

date, no clinical research has been performed to assess its diagnostic effectiveness in embryos. Patients need to be properly informed on the limitations of this use of PRSs, and a societal

debate, focused on what would be considered acceptable with regard to the selection of individual traits, should take place before any further implementation of the technique in this

population. INTRODUCTION Polygenic risk scores (PRSs) are estimates of an individual’s susceptibility to a specific complex trait obtained by aggregating the effects of dozens, thousands,

and potentially millions of genetic variants associated with that specific trait into a single figure. Some private companies have begun to market PRS analyses on embryos to prospective

parents through the use of in vitro fertilisation and pre-implantation genetic testing (PGT; PGT-P) [1,2,3,4] This practice raises many concerns. Complex traits are determined by a

combination of genes and environment, and PRSs can only capture a part of the genetic component – that which is derived from the cumulative effects of many genetic variants of small

individual effect. PRSs themselves should be calculated using their effects from the ethnic group the parents belong to. The estimation of PRSs for children of parents from diverse ethnic

origins is not yet possible to determine correctly. For risks to be calculated as accurately as possible, PRSs should be combined with the effects of non-genetic factors from an individual’s

life history such as environment, nutrition, and physical activity. Furthermore, the effects of the genetic factors may interact with each other as well as with changes in lifestyle and

clinical risk factors throughout an individual’s life, and these interactions may be difficult to account for when calculating the PRS. The concomitant occurrence of rare genetic variants of

major effect, whose presence might be unknown, can influence hugely the calculation of the PRS, thus introducing an additional layer of complexity. THE PRS SITUATION TODAY—USES AND

LIMITATIONS Currently, PRS assessments capture only a fraction of the total estimated heritable component of a trait [5, 6], partly because they are determined using only a limited number of

polymorphic variants in certain genes. The PRSs are commonly calculated as a weighted sum of the number of disease risk (increasing/decreasing) variants carried by an individual, where the

risk variants and their weighting, derived from genome-wide association studies (GWASs) [7, 8], may not be the relevant genetic factors but simply located nearby, thus introducing

uncertainty in the estimates of effect size associated with individual variants in PRS. The GWASs are typically carried out in populations of defined ancestry (commonly European) and the

data extrapolated from those studies might not be valid for populations of different ancestries. As such their general applicability can also be limited. Importantly, individual variants may

increase the risk for one trait, while simultaneously reducing the risk of another. This complexity is often not obvious to individuals who request information about their future risk

through PRS, because they are only informed about the risk for a specific trait that they have sought advice for. They are therefore not provided with data about the risks or benefits of

another trait influenced by the same variants, which may or may not be known and might also have included those with effects on prenatal development. Given the many limitations summarised

above, PRSs are not used in clinics. However, it seems plausible that, in the near future, some may be introduced into clinical assessment with the aim of improving the identification of

at-risk individuals, and treatment for specific conditions [9, 10]. However, this would not necessarily be translated into implementation for prenatal diagnostics. In a proper clinical or

research setting, an assessment of all potential contributory risks, including genetic and environmental ones, would be undertaken and made available. Outside this framework, and especially

when PRS assessments are provided as direct-to-consumer tests, their evaluation of a patient’s risk may be dangerously incomplete and can lead to grave misunderstandings [1, 11].

Extrapolating the results from predictive assessments in adult cohorts to use them as a factor for embryo screening would be improper. No clinical research protocol has been performed so far

to assess the diagnostic effectiveness of PRSs in embryos. Were these be established, it would take many years to obtain reliable results, given that one might have to wait decades for

people to develop, for example, early-onset Alzheimer’s disease. THE USE OF PRS IN EMBRYO SCREENING AND SELECTION While it is relatively common for parents to consider any genetic risks they

may pass on to their children, this is normally undertaken via the proven practice of carrier screening and genetic testing for inherited Mendelian disorders. In these cases, the ability of

the test to predict the development of the disease is usually very high. In fact, when a genetic condition has an extremely low penetrance (the proportion of people with a particular

genetic variant who exhibit signs and symptoms of a genetic disorder is low), it is very rare that the prospective parents would even consider prenatal or pre-implantation testing. When

applied to the selection of embryos for transfer, the PRS will relate to an individual family and not to a wide population. The intrafamilial variability would be much more limited than in

the wider population, and therefore the PRS would be unlikely to be useful in determining the choice of one embryo over another, particularly as the number of viable embryos available is

typically very small. Even if a discrete difference exists between two or more viable embryos suitable for transfer, a particular combination of genetic variants detected and evaluated would

not provide a definitive diagnosis. Such a set of variants will correspond at best to a small increase in an individual’s risk, relative to the population’s risk for a complex trait, if the

prediction is based on estimates for an ethnic group (ancestry) corresponding to that of the parents. In addition, if the selection were aimed at more than one PRS per embryo, it is easy to

estimate by simple probability that the total number of embryos needed to be examined in order to find at least one (if any) suitable embryos to transfer would be unrealistic for our

species and would also be unethical. Overall, adding PRSs to PGT would amount to a form of embryo screening. The criteria to assess and implement a screening programme would include, among

others, the proportionality principle, according to which “the possible benefits of the screening should clearly outweigh its possible disadvantages”. For the assessment of the

proportionality of PRSs in PGT, it is important to take account of tensions with other parameters, more important for ranking embryos for transfer. Such parameters include viability scores

and implications for the complex counselling process, especially when the values of professionals and customers for embryo ranking do not match. Research on PRSs is not aimed at the

development of pre-symptomatic tests in embryos but rather at the advancement of understanding of disease mechanisms, and the management and treatment of liveborn individuals, most

frequently when they reach their adulthood. For PRS research, the aim is different, the population is different, the setting is different from what is expected from PGT. PROTECTING

PROSPECTIVE PARENTS, THEIR OFFSPRING, AND SOCIETY At present, carrying out a PRS test for embryo selection would be premature at best. Prospective parents and the public must be provided

with adequate and unbiased information on the risks and limitations of such a practice [12]. It will be vital that a societal debate takes place before any potential application of the

technique, and this should be focused on what would be considered acceptable with regard to the selection of individual traits, in particular. Without proper public engagement and oversight,

the practice of implementing PRS test for embryo selection could easily lead to discrimination and the stigmatisation of certain conditions. Further studies are needed to understand which

and how polygenic risk estimates for common diseases can be implemented in clinical care. Such research should disentangle the complex interplay between PRSs for a range of conditions and

the environment. More studies are needed to understand the biology of normal embryonic and foetal development, as well as its interplay with the intrauterine environment, which is still so

elusive. For the time being, it is important for reasons of justice to assess whether public and individual resources can be better used to improve our knowledge on PRSs and their

relationships with the environment in which we live, rather than on the premature application of an inadequately evaluated test to our future children. CHANGE HISTORY * _ 14 MARCH 2022 A

Correction to this paper has been published: https://doi.org/10.1038/s41431-022-01067-0 _ * _ 19 AUGUST 2022 A Correction to this paper has been published:

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media coverage. BMC Med Ethics. 2021;22:125. Article  Google Scholar  Download references FUNDING IP has received funding from the World Cancer Research Fund (WCRF UK) and World Cancer

Research Fund International (2017/1641), the European Union’s Horizon 2020 research and innovation programme (LONGITOOLS, H2020-SC1-2019-874739), the Ministry of Science and Higher Education

of Russian Federation (075-15-2021-595), Agence Nationale de la Recherche (PreciDIAB, ANR-18-IBHU-0001), the European Union through the “Fonds européen de développement regional” (FEDER),

the “Conseil Régional des Hauts-de-France” (Hauts-de-France Regional Council), and the “Métropole Européenne de Lille” (MEL, European Metropolis of Lille). AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Clinical Genetics Department, Guy’s and St Thomas NHS Foundation Trust, London, UK Francesca Forzano * Department of Medical Genetics, Medical University of Sofia, Sofia,

Bulgaria Olga Antonova * Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, Wales, UK Angus Clarke * Maastricht University, Maastricht, The Netherlands Guido

de Wert * Human Genetics, Heidelberg, Germany Sabine Hentze * Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s University of London, London, UK Yalda Jamshidi

 & Yalda Jamshidi * University of Leuven ESAT-STADIUS, B-3001, Leuven, Belgium Yves Moreau * Finnish Institute for Health and Welfare (THL), Biomedicum 1, Haartmaninkatu 8, 00290,

Helsinki, Finland Markus Perola * Department of Clinical & Experimental Medicine, University of Surrey, Guildford, UK Inga Prokopenko * UMR 8199 - EGID, Institut Pasteur de Lille, CNRS,

University of Lille, F-59000, Lille, France Inga Prokopenko * Institute of Biochemistry and Genetics, Ufa Federal Research Centre, Russian Academy of Sciences, Ufa, Russian Federation Inga

Prokopenko * Centre for Genomic Medicine, St Mary’s Hospital, Manchester, M13 0JH, England Andrew Read * Center for Integrative Genomics, University of Lausanne, CH-1015, Lausanne,

Switzerland Alexandre Reymond * Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik, Iceland Vigdis Stefansdottir * Section Community Genetics,

Department of Clinical Genetics and Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands Carla van El * UOC Genetica Medica,

Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy Maurizio Genuardi * Sezione di Medicina Genomica, Dipartimento

di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy Maurizio Genuardi * Clinical Institute for Genomic Medicine, University Medical Center Ljubljana,

Ljubljana, Slovenia Borut Peterlin & Karin Writzl * Department of Pathology, Faculty of Medicine, University of Porto, PT, Porto, Portugal Carla Oliveira * Instituto de Investigação e

Inovação em Saúde (i3S), University of Porto, PT, Porto, Portugal Carla Oliveira * Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), University of Porto,

PT, Porto, Portugal Carla Oliveira * Department of Medical Genetics, Haukeland University Hospital, 5021, Bergen, Norway Gunnar Douzgos Houge * Department of Genetics, SYNLAB Suisse SA,

Chemin d’Entre Bois 21, 1018, Lausanne, Switzerland Christophe Cordier * Researcher Medical Ethics, Lund University, Uppsala, Sweden Heidi Howard * Chalmers University (part of GENIE

initiative), Uppsala, Sweden Heidi Howard * Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, Prague,

CZ15006, Czech Republic Milan Macek * Department of Medical Genetics, University of Pécs, Szigeti 12., H-7624, Pécs, Hungary Béla Melegh * UnIGENe and Centre for Predictive and Preventive

Genetics, IBMC—Institute for Molecular and Cell Biology, i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal Alvaro Mendes * Laboratory for Molecular

Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia Dragica Radojkovic * CERPOP, UMR 1295, Inserm, CERPOP, UMR 1295, Inserm, Université

de Toulouse-Université Paul Sabatier-Toulouse III, Responsable Equipe BIOETHICS: Trajectoires d’innovations en santé:enjeux bioéthiques et sociétaux, Toulouse, France Emmanuelle Rial-Sebbag

* Plateforme Sociétale “Génétique et Société, GIS Genotoul, Génopole Toulouse Midi-Pyrénées, 37, allées Jules Guesde, 31073, Toulouse Cedex, France Emmanuelle Rial-Sebbag * Manchester

Centre of Health Psychology, Division of Psychology and Mental Health, School of Health Sciences, Manchester Academic Health Science Centre, University of Manchester, Coupland Street,

Manchester, M13 9PL, England Fiona Ulph Authors * Francesca Forzano View author publications You can also search for this author inPubMed Google Scholar * Olga Antonova View author

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You can also search for this author inPubMed Google Scholar * Maurizio Genuardi View author publications You can also search for this author inPubMed Google Scholar CONSORTIA ON BEHALF OF

THE EXECUTIVE COMMITTEE OF THE EUROPEAN SOCIETY OF HUMAN GENETICS * Maurizio Genuardi * , Borut Peterlin * , Andrew Read * , Alexandre Reymond * , Carla Oliveira * , Karin Writzl *  & 

Gunnar Douzgos Houge THE PUBLIC AND PROFESSIONAL POLICY COMMITTEE OF THE EUROPEAN SOCIETY OF HUMAN GENETICS * Francesca Forzano * , Angus Clarke * , Christophe Cordier * , Guido de Wert * , 

Sabine Hentze * , Heidi Howard * , Milan Macek * , Béla Melegh * , Alvaro Mendes * , Yves Moreau * , Markus Perola * , Inga Prokopenko * , Dragica Radojkovic * , Emmanuelle Rial-Sebbag * , 

Maurizio Genuardi * , Fiona Ulph * , Carla van El * , Olga Antonova *  & Yalda Jamshidi CONTRIBUTIONS FF has drafted the paper. All the co-authors have contributed to implement and

finalise the draft. All the members of the Exec Committee and of the PPPC have reviewed and endorsed the manuscript. CORRESPONDING AUTHOR Correspondence to Francesca Forzano. ETHICS

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permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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_ 30, 493–495 (2022). https://doi.org/10.1038/s41431-021-01000-x Download citation * Received: 16 October 2021 * Accepted: 28 October 2021 * Published: 17 December

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