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ToolsGoode, Elizabeth C., Fachal, Laura, Panousis, Nikolaos, Moutsianas, Loukas, McIntyre, Rebecca E., Bai, Benjamin Yu Hang, Kawasaki, Norihito, Wittmann, Alexandra, Raine, Tim, Rushbrook, Simon M. and Anderson, Carl A. (2024) Fine-mapping and molecular characterisation of primary sclerosing cholangitis genetic risk loci. Nature Communications, 15 (1). ISSN 2041-1723
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Abstract
Genome-wide association studies of primary sclerosing cholangitis have identified 23 susceptibility loci. The majority of these loci reside in non-coding regions of the genome and are thought to exert their effect by perturbing the regulation of nearby genes. Here, we aim to identify these genes to improve the biological understanding of primary sclerosing cholangitis, and nominate potential drug targets. We first build an eQTL map for six primary sclerosing cholangitis-relevant T-cell subsets obtained from the peripheral blood of primary sclerosing cholangitis and ulcerative colitis patients. These maps identify 10,459 unique eGenes, 87% of which are shared across all six primary sclerosing cholangitis T-cell types. We then search for colocalisations between primary sclerosing cholangitis loci and eQTLs and undertake Bayesian fine-mapping to identify disease-causing variants. In this work, colocalisation analyses nominate likely primary sclerosing cholangitis effector genes and biological mechanisms at five non-coding (UBASH3A, PRKD2, ETS2 and AP003774.1/CCDC88B) and one coding (SH2B3) primary sclerosing cholangitis loci. Through fine-mapping we identify likely causal variants for a third of all primary sclerosing cholangitis-associated loci, including two to single variant resolution.
| Item Type: | Article |
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| Additional Information: | Data availability: Full summary statistics (nominal and permuted files) for data generated in this study are now available via Zenodo under accession code 10.5281/zenodo.11143561 [https://zenodo.org/records/11143561]. Expression data (cram files), and genotyping array data (plink format,.bed.bim.fam, as well as.idat and.gtc files) are shared via EGA (genotyping array data under Study Accession Number: EGAS00001002643; expression data under Study Accession Number: EGAS00001002642). Source data for the patient characteristics are provided with this paper in the accompanying Source Data file. Previously published data used in this study can be accessed through the GWAS catalogue: Cordell et al.63 2015 PBC GWAS is available at https://www.ebi.ac.uk/gwas/publications/26394269 Bradfield et al.46 2011 T1DM GWAS is available at https://www.ebi.ac.uk/gwas/publications/21980299 Trynka 2011 et al.28 CeD GWAS is available at https://www.ebi.ac.uk/gwas/publications/22057235 Ocada 2014 et al. RhA GWAS is available at https://www.ebi.ac.uk/gwas/publications/24390342 Beecham 2013 et al.65 MS GWAS is available at https://www.ebi.ac.uk/gwas/publications/24076602 Bentham 2015 et al. SLE GWAS is available at https://www.ebi.ac.uk/gwas/publications/26502338 Astle et al.66 2016 GWAS of lymphocyte, neutrophil and monocyte counts is available at https://www.ebi.ac.uk/gwas/publications/27863252 (monocyte counts: https://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST004001-GCST005000/GCST004625/mono_Jan2018_update/; leucocyte count: https://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST004001-GCST005000/GCST004610/wbc_Jan2018_update/; neutrophil counts: https://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST004001-GCST005000/GCST004629/neut_Jan2018_update/), De Lange et al.62 2017 IBD GWAS is available at https://ftp.sanger.ac.uk/pub/project/humgen/summary_statistics/human/2016-11-07/. GTEx V7 bulk tissue expression for liver, transverse colon, sigmoid colpon, terminal ileum, whole blood and RBV-transformd lymphocytes are available from the GTEx portal [https://gtexportal.org/home/downloads/adult-gtex/bulk_tissue_expression] The EGA Blueprint data for expression in naive T-cells, neutrophils and monocytes is available under accession number EGAD00001005199 Macromap data for expression of IPS-derived macrophages in multiple stimulation states is available on Zenodo [https://zenodo.org/records/7967759] Kim-Hellmuth et al.83 2017 expression data in monocytes is available under accession number E-MTAB-5631 Source data are provided with this paper. |
| Uncontrolled Keywords: | general chemistry,general biochemistry,genetics and molecular biology,general,general physics and astronomy ,/dk/atira/pure/subjectarea/asjc/1600/1600 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 14 Aug 2026 15:43 |
| Last Modified: | 14 Aug 2026 15:43 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/104160 |
| DOI: | 10.1038/s41467-024-53602-w |
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