Pleiotropic Expression Quantitative Trait Loci Are Enriched in Enhancers and Transcription Factor Binding Sites and Impact More Genes

Integrating expression quantitative trait loci (eQTL) data with genome-wide association studies (GWAS) enables the discovery of pleiotropic gene regulatory variants that influence a wide range of traits and disease susceptibilities. However, a comprehensive understanding of the distribution of pleiotropic QTLs across the genome and their phenotypic associations remain limited. In this study, we systematically annotated genetic variants associated with both trait variation and gene expression changes, focusing specifically on the unique characteristics of pleiotropic eQTLs. By integrating data from 127 eQTL studies and 417 traits from the IEU Open GWAS Project, we identified 476 pleiotropic eQTL variants affecting two or more distinct traits. Our analysis highlighted 5,345 eQTL candidates potentially linked to gene expression changes across 293 GWAS traits. Notably, the 476 pleiotropic eQTLs associated with multiple trait categories were localized within a cumulative 2.5 Mbp genomic region. These pleiotropic eQTLs were enriched in enhancer regions and CTCF loops, influencing a larger number of genes in closer genomic proximity. Our findings reveal that pleiotropic eQTLs are concentrated within a small fraction of the genome and exhibit distinct molecular features.

Colocalization results are accessible through an interactive web application and UCSC genome browser tracks at https://gwas2eqtl.tagc.univ-amu.fr/gwas2eqtl, facilitating the exploration of pleiotropic eQTLs and their roles in gene regulation and disease susceptibility.