SEAHORSE: A Serendipity Engine Assaying Heterogeneous Omics-Related Sampling Experiments

Abstract

Large public molecular atlases such as the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA) invite systematic discovery, yet most analyses remain hypothesis-driven and interrogate a tiny fraction of possible relationships among phenotypic, clinical, and molecular variables. We developed SEAHORSE (Serendipity Engine Assaying Heterogeneous Omics-Related Sampling Experiments), a discovery engine and accompanying R package that exhaustively precomputes all pairwise associations across heterogeneous data types and presents them as a searchable association landscape. Using GTEx (948 donors, 43 tissues, 154 phenotypes), SEAHORSE generated 341,008 phenotype-phenotype associations, 125,246,938 phenotype-gene associations, and 10,269,910,410 gene-gene correlations. In parallel analyses spanning 33 tumor types in TCGA, SEAHORSE generated 625,042 phenotype-phenotype associations, 183,080,369 phenotype-gene associations, and 12,096,948,950 gene-gene correlations. Across GTEx, height was repeatedly associated with enrichment of transcriptional programs, most strikingly the Kyoto Encyclopedia of Genes and Genomes (KEGG) term "Pathways in Cancer," significant in 17 tissues, offering a molecular entry point into long-reported links between stature and cancer risk. Height was also associated with immune, cardiovascular, and neurologic programs. In TCGA, age was consistently associated with WNT signaling, translation, cell differentiation, and cell cycle programs across tumors. These findings illustrate a new paradigm: large cohorts should be treated not merely as repositories for testing preconceived hypotheses but as association landscapes that can generate unexpected biological hypotheses.