Dataset Information

Multitrait genome-wide analyses identify new susceptibility loci and candidate drugs to primary sclerosing cholangitis.

ABSTRACT: Primary sclerosing cholangitis (PSC) is a rare autoimmune bile duct disease that is strongly associated with immune-mediated disorders. In this study, we implemented multitrait joint analyses to genome-wide association summary statistics of PSC and numerous clinical and epidemiological traits to estimate the genetic contribution of each trait and genetic correlations between traits and to identify new lead PSC risk-associated loci. We identified seven new loci that have not been previously reported and one new independent lead variant in the previously reported locus. Functional annotation and fine-mapping nominated several potential susceptibility genes such as MANBA and IRF5. Network-based in silico drug efficacy screening provided candidate agents for further study of pharmacological effect in PSC.

SUBMITTER: Han Y

PROVIDER: S-EPMC9958016 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Multitrait genome-wide analyses identify new susceptibility loci and candidate drugs to primary sclerosing cholangitis.

Han Younghun Y Byun Jinyoung J Zhu Catherine C Sun Ryan R Roh Julia Y JY Cordell Heather J HJ Lee Hyun-Sung HS Shaw Vikram R VR Kang Sung Wook SW Razjouyan Javad J Cooley Matthew A MA Hassan Manal M MM Siminovitch Katherine A KA Folseraas Trine T Ellinghaus David D Bergquist Annika A Rushbrook Simon M SM Franke Andre A Karlsen Tom H TH Lazaridis Konstantinos N KN McGlynn Katherine A KA Roberts Lewis R LR Amos Christopher I CI

Nature communications 20230224 1

Primary sclerosing cholangitis (PSC) is a rare autoimmune bile duct disease that is strongly associated with immune-mediated disorders. In this study, we implemented multitrait joint analyses to genome-wide association summary statistics of PSC and numerous clinical and epidemiological traits to estimate the genetic contribution of each trait and genetic correlations between traits and to identify new lead PSC risk-associated loci. We identified seven new loci that have not been previously repor ...[more]

PMID: 36828809

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Project description:Backgrounds & aimsPrimary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening.MethodsWe combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts.ResultsWe identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders.ConclusionsThis study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders.Lay summaryPrimary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these 'candidate genes' to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC.

Dataset Information

Multitrait genome-wide analyses identify new susceptibility loci and candidate drugs to primary sclerosing cholangitis.

Publications

Multitrait genome-wide analyses identify new susceptibility loci and candidate drugs to primary sclerosing cholangitis.

Similar Datasets

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