Over the recent decades, genome-wide association studies (GWAS) have dramatically changed the understanding of human genetics. A recent genetic data release by UK Biobank (UKB) has allowed many researchers worldwide to have comprehensive look into the genetic architecture of thousands of human phenotypes. In this study, we used GWAS summary statistics derived from the UKB cohort to investigate functional mechanisms of pleiotropic effects across the human phenome. We find that highly pleiotropic variants often correspond to broadly expressed genes with ubiquitous functions, such as matrisome components and cell growth regulators; and tend to colocalize with tissue-shared eQTLs. At the same time, signaling pathway components are more prevalent among highly pleiotropic genes compared to regulatory proteins such as transcription factors. Our results suggest that protein-level pleiotropy mediated by ubiquitously expressed genes is the most prevalent mechanism of pleiotropic genetic effects across the human phenome.
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