GEM-Finder: dissecting GWAS variants via long-range interacting cis-regulatory elements with differentiation-specific genes

Interpreting the functional significance of non-coding GWAS variants remains challenging. While co-localizing variants with cell-type specific cis-regulatory elements (CREs) has improved our understanding, many variants remain unassociated. In this study, we propose GEM-Finder (Genomic Element Mapping for Fine Discovery of Promoter-Linked Variants), a novel analytical framework that integrates transcriptomic, epigenomic (H3K27ac ChIP-seq), and chromatin interaction data. GEM-Finder utilizes long-range chromatin interactions to identify CREs that connect differentially expressed genes of specific cell types. When we apply GEM-Finder to endothelial differentiation, unlike conventional methods primarily focused on cell-type specific CREs, GEM-Finder identifies 7.6 times more disease/trait associations. Specifically, by integrating transcriptome, epigenome (particularly H3K27ac ChIP-seq), and long-range chromatin interactions during endothelial differentiation, we identified CREs linked to differentiation-specific genes. Our enrichment analyses revealed both shared and unique associations for 53 human diseases/traits. Notably, the majority of these (68%) exhibited unique associations in a differentiation-specific manner. Hematological traits and neuropsychiatric disorders were primarily linked to the final stage of endothelial differentiation, while several complex diseases, such as colorectal cancer (CRC), were unexpectedly associated with the late stage. Our findings underscore the importance of leveraging long-range chromatin interactions to accurately identify disease-associated CREs in the functional characterization of non-coding GWAS variants.