Expanding drug targets for 112 chronic diseases using a machine learning-assisted genetic priority score

Chen, Robert, Duffy, Áine, Petrazzini, Ben O., Vy, Ha My, Stein, David, Mort, Matthew ORCID: https://orcid.org/0000-0002-3986-0935, Park, Joshua K., Schlessinger, Avner, Itan, Yuval, Cooper, David N. ORCID: https://orcid.org/0000-0002-8943-8484, Jordan, Daniel M., Rocheleau, Ghislain and Do, Ron 2024. Expanding drug targets for 112 chronic diseases using a machine learning-assisted genetic priority score. Nature Communications 15 (1) , 8891. 10.1038/s41467-024-53333-y

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Abstract

Identifying genetic drivers of chronic diseases is necessary for drug discovery. Here, we develop a machine learning-assisted genetic priority score, which we call ML-GPS, that incorporates genetic associations with predicted disease phenotypes to enhance target discovery. First, we construct gradient boosting models to predict 112 chronic disease phecodes in the UK Biobank and analyze associations of predicted and observed phenotypes with common, rare, and ultra-rare variants to model the allelic series. We integrate these associations with existing evidence using gradient boosting with continuous feature encoding to construct ML-GPS, training it to predict drug indications in Open Targets and externally testing it in SIDER. We then generate ML-GPS predictions for 2,362,636 gene-phecode pairs. We find that the use of predicted phenotypes, which identify substantially more genetic associations than observed phenotypes across the allele frequency spectrum, significantly improves the performance of ML-GPS. ML-GPS increases coverage of drug targets, with the top 1% of all scores providing support for 15,077 gene-phecode pairs that previously had no support. ML-GPS can also identify well-known target-disease relationships, promising targets without indicated drugs, and targets for several drugs in clinical trials, including LRRK2 inhibitors for Parkinson’s disease and olpasiran for cardiovascular disease.

Item Type:	Article
Date Type:	Published Online
Status:	Published
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:	16 October 2024
Date of Acceptance:	9 October 2024
Last Modified:	01 Nov 2024 14:33
URI:	https://orca.cardiff.ac.uk/id/eprint/172932

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