Scaling genetic discovery through automated post-GWAS interpretation

Abstract

Genome-wide association studies (GWAS) have made association discovery systematic and cumulative, yet evidence for interpreting associated loci remains selective, heterogeneous and difficult to accumulate across studies. Here we present Post-GWAS Intelligence (PGI), which couples context-dependent post-GWAS analysis to a common representation of analysis-derived evidence. Its multi-agent engine, VariantAgent, executes workflows, records tool-derived results in standardized variant-centred units and generates trait-level interpretations linked to their analytical basis and evidential status. Complementary benchmarks showed that VariantAgent outperformed tested general-purpose and biomedical agents, with its largest advantage when success required both a correct answer and a valid analytical trace. Across 34 published GWAS, VariantAgent achieved a mean per-study recovery of 82.1% for directly comparable findings. The largest gains lay downstream of association mapping, where uniform analysis extended published interpretations and identified regulatory relationships at established risk loci not previously reported in the source studies. Analysis of 1,041 GWAS yielded 530,949 evidence units and corresponding reports, which PGI organized into a cross-trait catalogue. Catalogue interrogation resolved an apparent cross-trait overlap into distinct signals and trait-specific biological hypotheses. This work demonstrates how PGI can extend genetic discovery beyond association mapping by enabling biological evidence to accumulate across studies.