The Human Pleiotropic Map of GWAS Associations and Therapeutic Implications

Abstract

Genetic support for drug targets substantially increases clinical success rates, establishing genome-wide 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.