Author information

• ¹Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
• ²Genome Medical Science Project, National Center for Global Health and Medicine (NCGM), Tokyo, Japan.
• ³Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Omura, Japan.
• ⁴Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
• ⁵Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan; Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
• ⁶Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Shanghai, China.
• ⁷Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China; Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China.
• ⁸Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America.
• ⁹Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America.
• ¹⁰Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy.
• ¹¹Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy.
• ¹²Regeneron Genetics Center, Tarrytown, New York, United States of America.
• ¹³Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
• ¹⁴Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
• ¹⁵Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas, United States of America.
• ¹⁶Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada.
• ¹⁷University of California, Davis, California, United States of America.
• ¹⁸Departments of Medicine, Immunology and Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada.
• ¹⁹Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom. Electronic address: gfm26@cam.ac.uk.

Abstract

Background & aims: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic 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.

Methods: We combined new and existing genotype data for 10,516 cases and 20,772 controls from five European and two East Asian cohorts.

Results: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57^th 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, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of T_H1 and T_H17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders.

Conclusions: This 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 summary: Primary 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, UK, or 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.

Clinical trial number: Not applicable.