Genetically regulated eRNA expression predicts chromatin contact frequency and reveals genetic mechanisms at GWAS loci
Abstract The biological functions of extragenic enhancer RNAs and their impact on disease risk remain relatively underexplored. In this work, we develop in silico models of genetically regulated expression of enhancer RNAs across 49 cell and tissue types, characterizing their degree of genetic contr...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58023-x |
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| author | Michael J. Betti Phillip Lin Melinda C. Aldrich Eric R. Gamazon |
| author_facet | Michael J. Betti Phillip Lin Melinda C. Aldrich Eric R. Gamazon |
| author_sort | Michael J. Betti |
| collection | DOAJ |
| description | Abstract The biological functions of extragenic enhancer RNAs and their impact on disease risk remain relatively underexplored. In this work, we develop in silico models of genetically regulated expression of enhancer RNAs across 49 cell and tissue types, characterizing their degree of genetic control. Leveraging the estimated genetically regulated expression for enhancer RNAs and canonical genes in a large-scale DNA biobank (N > 70,000) and high-resolution Hi-C contact data, we train a deep learning-based model of pairwise three-dimensional chromatin contact frequency for enhancer-enhancer and enhancer-gene pairs in cerebellum and whole blood. Notably, the use of genetically regulated expression of enhancer RNAs provides substantial tissue-specific predictive power, supporting a role for these transcripts in modulating spatial chromatin organization. We identify schizophrenia-associated enhancer RNAs independent of GWAS loci using enhancer RNA-based TWAS and determine the causal effects of these enhancer RNAs using Mendelian randomization. Using enhancer RNA-based TWAS, we generate a comprehensive resource of tissue-specific enhancer associations with complex traits in the UK Biobank. Finally, we show that a substantially greater proportion (63%) of GWAS associations colocalize with causal regulatory variation when enhancer RNAs are included. |
| format | Article |
| id | doaj-art-084e483513df41e1bd8b2324da265b37 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-084e483513df41e1bd8b2324da265b372025-08-20T01:54:26ZengNature PortfolioNature Communications2041-17232025-04-0116111510.1038/s41467-025-58023-xGenetically regulated eRNA expression predicts chromatin contact frequency and reveals genetic mechanisms at GWAS lociMichael J. Betti0Phillip Lin1Melinda C. Aldrich2Eric R. Gamazon3Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical CenterDepartment of Medicine, Division of Genetic Medicine, Vanderbilt University Medical CenterDepartment of Medicine, Division of Genetic Medicine, Vanderbilt University Medical CenterDepartment of Medicine, Division of Genetic Medicine, Vanderbilt University Medical CenterAbstract The biological functions of extragenic enhancer RNAs and their impact on disease risk remain relatively underexplored. In this work, we develop in silico models of genetically regulated expression of enhancer RNAs across 49 cell and tissue types, characterizing their degree of genetic control. Leveraging the estimated genetically regulated expression for enhancer RNAs and canonical genes in a large-scale DNA biobank (N > 70,000) and high-resolution Hi-C contact data, we train a deep learning-based model of pairwise three-dimensional chromatin contact frequency for enhancer-enhancer and enhancer-gene pairs in cerebellum and whole blood. Notably, the use of genetically regulated expression of enhancer RNAs provides substantial tissue-specific predictive power, supporting a role for these transcripts in modulating spatial chromatin organization. We identify schizophrenia-associated enhancer RNAs independent of GWAS loci using enhancer RNA-based TWAS and determine the causal effects of these enhancer RNAs using Mendelian randomization. Using enhancer RNA-based TWAS, we generate a comprehensive resource of tissue-specific enhancer associations with complex traits in the UK Biobank. Finally, we show that a substantially greater proportion (63%) of GWAS associations colocalize with causal regulatory variation when enhancer RNAs are included.https://doi.org/10.1038/s41467-025-58023-x |
| spellingShingle | Michael J. Betti Phillip Lin Melinda C. Aldrich Eric R. Gamazon Genetically regulated eRNA expression predicts chromatin contact frequency and reveals genetic mechanisms at GWAS loci Nature Communications |
| title | Genetically regulated eRNA expression predicts chromatin contact frequency and reveals genetic mechanisms at GWAS loci |
| title_full | Genetically regulated eRNA expression predicts chromatin contact frequency and reveals genetic mechanisms at GWAS loci |
| title_fullStr | Genetically regulated eRNA expression predicts chromatin contact frequency and reveals genetic mechanisms at GWAS loci |
| title_full_unstemmed | Genetically regulated eRNA expression predicts chromatin contact frequency and reveals genetic mechanisms at GWAS loci |
| title_short | Genetically regulated eRNA expression predicts chromatin contact frequency and reveals genetic mechanisms at GWAS loci |
| title_sort | genetically regulated erna expression predicts chromatin contact frequency and reveals genetic mechanisms at gwas loci |
| url | https://doi.org/10.1038/s41467-025-58023-x |
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