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  • Review Article
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Genomics of drug target prioritization for complex diseases

Nature Reviews Genetics volume 27, pages 231–245 (2026)Cite this article

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Abstract

Drug development faces persistent challenges, with high attrition rates and unexpected adverse effects contributing to clinical trial failures. The recent convergence of large-scale biobanks, multi-omics data and computational methods, including machine learning, has led to advances in genetics-driven drug discovery, offering new opportunities to refine target selection and reduce late-stage risk. Integrating multiple lines of evidence centred on human genetics within a probabilistic framework enables the systematic prioritization of drug targets, prediction of adverse effects, and identification of drug repurposing opportunities. In this Review, we explore how these integrative approaches can address unmet clinical needs in diverse disease contexts, focusing on complex diseases.

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Fig. 1: Allelic series to infer direction and amount of therapeutic modulation.
Fig. 2: Machine learning approaches for phenotype extraction, imputation and augmentation.
Fig. 3: A unified probabilistic framework for drug target prioritization.

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Acknowledgements

R.D. is supported by the National Institute of General Medical Sciences of the NIH (R35-GM124836).

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Authors and Affiliations

  1. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Robert Chen, Áine Duffy & Ron Do

  2. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Robert Chen, Áine Duffy & Ron Do

  3. Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Robert Chen

  4. Windreich Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Robert Chen, Áine Duffy & Ron Do

  5. Center for Genomic Data Analytics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Áine Duffy & Ron Do

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R.D. is a scientific co-founder, consultant and equity holder for Pensieve Health (pending) and is a consultant for Variant Bio and Character Bio. A.D. is currently a full-time employee of GlaxoSmithKline.

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Chen, R., Duffy, Á. & Do, R. Genomics of drug target prioritization for complex diseases. Nat Rev Genet 27, 231–245 (2026). https://doi.org/10.1038/s41576-025-00904-4

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