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Clinical implementation of polygenic risk scores

European Journal of Human Genetics (2026)Cite this article

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A reply to: Horton. R., Dunlop. M., McCartney. M, et al. Promises Under Pressure: The Modest Predictive Power of Polygenic Risk Scores.

We thank Horton et al. [1] for their interest in our commentary on Polygenic Risk Scores (PRS) [2]. Whilst we understand some of their scepticism on the predictive power of PRS their response appears to lack balance. We understand their desire to temper our enthusiasm for PRS, but their comments do not appreciate the nuance in potential PRS usage. In particular, they focus on use of PRS as a stand-alone predictor of risk and criticise the discriminatory power. It was never our intention to recommend utilisation of PRS as a sole predictor of risk; it is best applied in combination with other risk factors [3].

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References

  1. Horton R, Dunlop M, McCartney M, Sud A, Sullivan R, Tomlinson. Promises under pressure: the modest predictive power of polygenic risk scores.

  2. Roberts E, Flaum N, Evans DG. Clinical implementation of polygenic risk scores. Eur J Hum Genet. 2025. https://doi.org/10.1038/s41431-025-01931-9.

  3. Evans DGR, van Veen EM, Harkness EF, Brentnall AR, Astley SM, Byers H, et al. Breast cancer risk stratification in women of screening age: incremental effects of adding mammographic density, polygenic risk, and a gene panel. Genet Med. 2022;24:1485–94.

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  5. Hindmarch S, Howell SJ, Usher-Smith JA, Gorman L, Evans DG, French DP. Feasibility and acceptability of offering breast cancer risk assessment to general population women aged 30-39 years: a mixed-methods study protocol. BMJ Open. 2024;14:e078555. https://doi.org/10.1136/bmjopen-2023-078555.

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Funding

This work was supported by the Manchester National Institute for Health Research Biomedical Research Centre (IS-BRC-1215-20007) and Cancer Research UK ACED International Alliance for Cancer Early Detection (C19941/A27859).

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Author notes

  1. These authors contributed equally: Eleanor Roberts, Nicola Flaum.

Authors and Affiliations

  1. Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    Eleanor Roberts & Nicola Flaum

  2. Manchester Breast Centre, The Christie, Manchester, UK

    Nicola Flaum & D. Gareth Evans

  3. Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester Academic Health Centre (MAHSC), Division of Evolution, Infection and Genomic Sciences, University of Manchester, Manchester, UK

    D. Gareth Evans

  4. Prevent Breast Cancer Prevention Centre, University Hospital of South Manchester NHS Trust, Wythenshawe, Manchester, UK

    D. Gareth Evans

  5. Manchester Centre for Genomic Medicine, St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK

    D. Gareth Evans

Authors
  1. Eleanor Roberts
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  2. Nicola Flaum
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  3. D. Gareth Evans
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Contributions

ER, NF, and DGE wrote the original draft, and reviewed and edited all drafts thereafter.

Corresponding author

Correspondence to D. Gareth Evans.

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Competing interests

DGE provides consultancy to Antegenes, otherwise the authors declare no competing interests.

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Roberts, E., Flaum, N. & Evans, D.G. Clinical implementation of polygenic risk scores. Eur J Hum Genet (2026). https://doi.org/10.1038/s41431-025-01999-3

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