Building The Human Genotype-Phenotype Map to Harness Pleiotropy and Refine Disease Mechanisms

Abstract Mapping the pleiotropic effect of genetic variation on biological processes and complex phenotypes is fundamental to extracting translational insight from genome-wide association studies (GWAS). Here we present The Human Genotype-Phenotype Map (GPMap), a repository of colocalizing genetic associations across 15,997 complex traits and 2.7 million molecular measurements, leveraging common and rare variants and cis -and trans -acting effects across disaggregated tissue types and single cell datasets to trace the complex pathways through which they act. We identify over 49.3 million colocalizing trait pairs, which aggregate into 97,393 colocalization groups, representing distinct pleiotropic variants based on shared genetic signals, with 55.8% of genome-wide significant disease-associated loci colocalizing with at least one molecular trait. This insight facilitates clustering of complex health and disease phenotypes based on genetic architecture, and the dissection of polygenic traits reflecting the composite impact of many underlying processes. We show that leveraging pleiotropic information can enhance the selection of genetic instruments for causal inference approaches and improves prediction of drug trial success. This open-source resource is available at https://gpmap.opengwas.io , with functionality for user GWAS upload.