Large-scale genomic and transcriptomic initiatives offer unprecedented ability to study the biology of complex traits and identify target genes for precision prevention or therapy. Translation to clinical contexts, however, has been slow and challenging due to lack of biological context for identified variant-level associations. Moreover, many translational researchers lack the computational or analytic infrastructures required to fully use these resources. We integrate genome-wide association study (GWAS) summary statistics from multiple publicly available sources and data from Genotype-Tissue Expression (GTEx) v8 using PrediXcan and provide a user-friendly platform for translational researchers based on state-of-the-art algorithms. We develop a novel Bayesian colocalization method, fastENLOC, to prioritize the most likely causal gene-trait associations. Our resource, PhenomeXcan, synthesizes 8.87 million variants from GWAS on 4,091 traits with transcriptome regulation data from 49 tissues in GTEx v8 into an innovative, gene-based resource including 22,255 genes. Across the entire genome/phenome space, we find 65,603 significant associations (Bonferroni-corrected p-value of 5.5 × 10−10), where 19,579 (29.8 percent) were colocalized (locus regional colocalization probability > 0.1). We successfully replicate associations from PheWAS Catalog (AUC=0.61) and OMIM (AUC=0.64). We provide examples of (a) finding novel and underreported genome-to-phenome associations, (b) exploring complex gene-trait clusters within PhenomeXcan, (c) studying phenome-to-phenome relationships between common and rare diseases via further integration of PhenomeXcan with ClinVar, and (d) evaluating potential therapeutic targets. PhenomeXcan ([phenomexcan.org][1]) broadens access to complex genomic and transcriptomic data and empowers translational researchers. One-Sentence Summary PhenomeXcan is a gene-based resource of gene-trait associations with biological context that supports translational research. [1]: http://phenomexcan.org

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