Fine-mapping and molecular characterisation of primary sclerosing cholangitis genetic risk loci.

Autor: Goode EC; Wellcome Sanger Institute, Hinxton, Cambridge, UK.; University of Cambridge, Cambridge, UK.; Norfolk and Norwich University Hospital, Norwich, UK., Fachal L; Wellcome Sanger Institute, Hinxton, Cambridge, UK., Panousis N; Wellcome Sanger Institute, Hinxton, Cambridge, UK., Moutsianas L; Wellcome Sanger Institute, Hinxton, Cambridge, UK., McIntyre RE; Wellcome Sanger Institute, Hinxton, Cambridge, UK., Bai BYH; Wellcome Sanger Institute, Hinxton, Cambridge, UK.; University of Cambridge, Cambridge, UK., Kawasaki N; Quadrum Institute, Norwich, UK., Wittmann A; Quadrum Institute, Norwich, UK., Raine T; University of Cambridge, Cambridge, UK., Rushbrook SM; Norfolk and Norwich University Hospital, Norwich, UK.; Norwich Medical School, University of East Anglia, Norwich, UK., Anderson CA; Wellcome Sanger Institute, Hinxton, Cambridge, UK. carl.anderson@sanger.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Nov 06; Vol. 15 (1), pp. 9594. Date of Electronic Publication: 2024 Nov 06.
DOI: 10.1038/s41467-024-53602-w
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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