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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. Our enrichment analyses reveal both shared and unique links across 53 human diseases/traits, uncovering novel associations between endothelial differentiation and various human diseases/traits. These findings underscore the importance of incorporating long-range chromatin interactions for a more precise identification of disease-associated CREs and functional characterization of non-coding GWAS variants.

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GEM-Finder: Dissecting GWAS Variants via Long-Range Interacting Cis-Regulatory Elements with Differentiationspecific Genes

  • 会议论文

  • 发表日期：

    2025年

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  • Gyeongsik Park,
  • Andrew J. Lee,
  • Inkyung Jung

摘要

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. Our enrichment analyses reveal both shared and unique links across 53 human diseases/traits, uncovering novel associations between endothelial differentiation and various human diseases/traits. These findings underscore the importance of incorporating long-range chromatin interactions for a more precise identification of disease-associated CREs and functional characterization of non-coding GWAS variants.