Beyond genome-wide association studies: Investigating the role of noncoding regulatory elements in primary sclerosing cholangitis
AuthorsPratt, Henry E
Elhajjajy, Shaimae I
Zhou, Jeffrey Y.
Pratt, Daniel S
Student AuthorsHenry Pratt
Academic ProgramMD/PhD; Bioinformatics and Computational Biology
UMass Chan AffiliationsBiochemistry and Molecular Biotechnology
Molecular, Cell and Cancer Biology
Morningside Graduate School of Biomedical Sciences
Program in Bioinformatics and Integrative Biology
Program in Innate Immunity
Document TypeJournal Article
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AbstractBackground: Genome-wide association studies (GWAS) have identified 30 risk loci for primary sclerosing cholangitis (PSC). Variants within these loci are found predominantly in noncoding regions of DNA making their mechanisms of conferring risk hard to define. Epigenomic studies have shown noncoding variants broadly impact regulatory element activity. The possible association of noncoding PSC variants with regulatory element activity has not been studied. We aimed to (1) determine if the noncoding risk variants in PSC impact regulatory element function and (2) if so, assess the role these regulatory elements have in explaining the genetic risk for PSC. Methods: Available epigenomic datasets were integrated to build a comprehensive atlas of cell type-specific regulatory elements, emphasizing PSC-relevant cell types. RNA-seq and ATAC-seq were performed on peripheral CD4+ T cells from 10 PSC patients and 11 healthy controls. Computational techniques were used to (1) study the enrichment of PSC-risk variants within regulatory elements, (2) correlate risk genotype with differences in regulatory element activity, and (3) identify regulatory elements differentially active and genes differentially expressed between PSC patients and controls. Results: Noncoding PSC-risk variants are strongly enriched within immune-specific enhancers, particularly ones involved in T-cell response to antigenic stimulation. In total, 250 genes and >10,000 regulatory elements were identified that are differentially active between patients and controls. Conclusions: Mechanistic effects are proposed for variants at 6 PSC-risk loci where genotype was linked with differential T-cell regulatory element activity. Regulatory elements are shown to play a key role in PSC pathophysiology.
SourcePratt HE, Wu T, Elhajjajy S, Zhou J, Fitzgerald K, Fazzio T, Weng Z, Pratt DS. Beyond genome-wide association studies: Investigating the role of noncoding regulatory elements in primary sclerosing cholangitis. Hepatol Commun. 2023 Sep 27;7(10):e0242. doi: 10.1097/HC9.0000000000000242. PMID: 37756045; PMCID: PMC10531193.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/52649
RightsThis is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.; Attribution 4.0 International
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Except where otherwise noted, this item's license is described as This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.