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

Younghun Han, Jinyoung Byun, Catherine Zhu, Ryan Sun, Julia Y. Roh, Heather J. Cordell, Hyun-Sung Lee, Vikram R. Shaw, Sung Wook Kang, Javad Razjouyan, Matthew A. Cooley, Manal M. Hassan, Katherine A. Siminovitch, Trine Folseraas, David Ellinghaus, Annika Bergquist, Simon M. Rushbrook, Andre Franke, Tom H. Karlsen, Konstantinos N. Lazaridis, Katherine A. McGlynn, Lewis R. Roberts and Christopher I. Amos ()
Additional contact information
Younghun Han: Baylor College of Medicine
Jinyoung Byun: Baylor College of Medicine
Catherine Zhu: Baylor College of Medicine
Ryan Sun: University of Texas, M.D. Anderson Cancer Center
Julia Y. Roh: Ochsner Health
Heather J. Cordell: Newcastle University
Hyun-Sung Lee: Baylor College of Medicine
Vikram R. Shaw: Baylor College of Medicine
Sung Wook Kang: Baylor College of Medicine
Javad Razjouyan: Michael E. DeBakey VA Medical Center
Matthew A. Cooley: Mayo Clinic
Manal M. Hassan: The University of Texas MD Anderson Cancer Center
Katherine A. Siminovitch: University of Toronto
Trine Folseraas: Oslo University Hospital Rikshospitalet
David Ellinghaus: Christian-Albrechts-University of Kiel
Annika Bergquist: Karolinska Institutet, Karolinska University Hospital
Simon M. Rushbrook: Norfolk and Norwich University Hospital
Andre Franke: Christian-Albrechts-University of Kiel
Tom H. Karlsen: Oslo University Hospital Rikshospitalet and University of Oslo
Konstantinos N. Lazaridis: Mayo Clinic
Katherine A. McGlynn: National Cancer Institute
Lewis R. Roberts: Oslo University Hospital Rikshospitalet and University of Oslo
Christopher I. Amos: Baylor College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36678-8

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