Development of a genetic priority score to predict drug side effects using human genetic evidence

Duffy, Áine, Chen, Robert, Stein, David, Park, Joshua K., Mort, Matthew ORCID: https://orcid.org/0000-0002-3986-0935, Verbanck, Marie, Schlessinger, Avner, Itan, Yuval, Cooper, David N. ORCID: https://orcid.org/0000-0002-8943-8484, Jordan, Daniel M., Rocheleau, Ghislain and Do, Ron 2025. Development of a genetic priority score to predict drug side effects using human genetic evidence. Nature Communications 16 (1) , 8713. 10.1038/s41467-025-63762-y

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Abstract

Many drug failures in clinical trials are due to inadequate safety profiles. We developed an in-silico side effect genetic priority score (SE-GPS) that leverages human genetic evidence to inform side effect risk for a given drug target. We construct the SE-GPS in the Open Target dataset using post-marketing side effect data, externally test it in OnSIDES using side effects reported from drug labels and then generate a SE-GPS for 19,422 protein coding genes and 502 phecodes, of which 1.7% had a SE-GPS > 0. To consider drug mechanism, we incorporated the direction of genetic effect into a directional version of the score called the SE-GPS-DOE. We observe that restricting to at least two lines of genetic evidence conferred a 2.3- and 2.5-fold increased risk in side effects in Open Targets and OnSIDES respectively, with increased enrichments in severe drugs. We make all predictions publicly available in a web portal.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc-nd/4.0/, Type: open-access
Publisher:	Nature Research
Date of First Compliant Deposit:	7 October 2025
Date of Acceptance:	27 August 2025
Last Modified:	07 Oct 2025 11:30
URI:	https://orca.cardiff.ac.uk/id/eprint/181523

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