The Human Pleiotropic Map of GWAS Associations and Therapeutic Implications

Genetic support for drug targets substantially increases clinical success rates, establishing genomewide association studies (GWAS) as central to therapeutic hypothesis generation. However, the same genetic evidence that reveals causal gene-disease relationships simultaneously exposes organism level safety liabilities - a dimension requiring principled, genome-wide quantification. Here we systematically analyse 100,526 GWAS to yield 789,453 credible sets and gene prioritisations for 15,641 genes, with discovery showing no saturation as GWAS expand and increase diversity. We find that 64% of GWAS-implicated genes are pleiotropic, associated with traits across multiple diseases and showing a non-linear relationship between the degree of pleiotropy and clinical success. Highly pleiotropic genes - concentrated in immune, inflammatory, and oncogenic signalling programmes - are enriched in safety-terminated clinical programmes, mouse lethal knockouts, and cancer driver genes, establishing gene-level pleiotropy as a potential measure of genetically-informed organism-level safety liability. Protein-altering variant (PAV) support amplifies therapeutic signal (OR = 6.0), yet PAV targets show higher average pleiotropy, introducing a competing safety liability. Combining PAV support with intermediate pleiotropy (2-5 therapeutic areas) resolves this tension, yielding OR = 10.3 and relative success = 4.8 - a profile already satisfied by 52 approved therapies. As GWAS continue to expand in scale and resolution, these findings lay the groundwork for increasingly sophisticated target discovery strategies that yield safer and more effective therapeutic hypotheses.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-05-01
DOI
https://doi.org/10.64898/2026.04.28.721048
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
0.00

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article

The Human Pleiotropic Map of GWAS Associations and Therapeutic Implications

Kaur Alasoo, Samuel Lessard, Vivien W. Ho, David G. Hulcoop et al.
bioRxiv (Cold Spring Harbor Laboratory)
Genetic Associations and Epidemiology
article

The Human Pleiotropic Map of GWAS Associations and Therapeutic Implications

Kaur Alasoo, Samuel Lessard, Vivien W. Ho, David G. Hulcoop, Helena Cornu, Irene López Santiago, Annalisa Buniello, Yakov A. Tsepilov, Ines Smit, Dániel Süveges, David Ochoa, Xiangyu Ge, Eric B. Fauman, Gosia Trynka, Laura Harris, Shameer Khader, Tobi Alegbe, Szymon Szyszkowski, Juan Maria Roldan-Romero, Ellen M. McDonagh, Ewan Birney, Clement Chatelain, Kirill Tsukanov, Yury S. Aulchenko, Mark I. McCarthy, Stephanie Yang, Anna O'Carroll, Alexander Predeus, Daniel Considine, Daniel Seaton, Polina Rusina
article en

Abstract

Genetic support for drug targets substantially increases clinical success rates, establishing genomewide association studies (GWAS) as central to therapeutic hypothesis generation. However, the same genetic evidence that reveals causal gene-disease relationships simultaneously exposes organism level safety liabilities - a dimension requiring principled, genome-wide quantification. Here we systematically analyse 100,526 GWAS to yield 789,453 credible sets and gene prioritisations for 15,641 genes, with discovery showing no saturation as GWAS expand and increase diversity. We find that 64% of GWAS-implicated genes are pleiotropic, associated with traits across multiple diseases and showing a non-linear relationship between the degree of pleiotropy and clinical success. Highly pleiotropic genes - concentrated in immune, inflammatory, and oncogenic signalling programmes - are enriched in safety-terminated clinical programmes, mouse lethal knockouts, and cancer driver genes, establishing gene-level pleiotropy as a potential measure of genetically-informed organism-level safety liability. Protein-altering variant (PAV) support amplifies therapeutic signal (OR = 6.0), yet PAV targets show higher average pleiotropy, introducing a competing safety liability. Combining PAV support with intermediate pleiotropy (2-5 therapeutic areas) resolves this tension, yielding OR = 10.3 and relative success = 4.8 - a profile already satisfied by 52 approved therapies. As GWAS continue to expand in scale and resolution, these findings lay the groundwork for increasingly sophisticated target discovery strategies that yield safer and more effective therapeutic hypotheses.

bioRxiv (Cold Spring Harbor Laboratory)
Merck & Co., Inc., Rahway, NJ, USA (United States) (US), European Bioinformatics Institute (GB), Target (United States) (US), Pfizer (United States) (US), Age UK (GB), Wellcome Sanger Institute (GB), Open Targets (GB), University of Tartu (EE)
National Human Genome Research Institute
Good health and well-being
Openalex Percentile: Top 10%
Genetic Associations and Epidemiology
DOIOpen Access PDFOpenAlex
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