Author information

• ¹Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital - Via Manzoni 56, 20089 Rozzano, Milan, Italy.
• ²Division 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.
• ³Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, NE1 3BZ, UK.
• ⁴Academic Department of Medical Genetics, Cambridge University, Cambridge, UK, CB2 0QQ.
• ⁵Faculty of Medical Sciences, Newcastle University, Newcastle, UK.
• ⁶Clinical Research Center, National Hospital Organization (NHO), Nagasaki Medical Center, and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Nagasaki, Japan.
• ⁷Genome Medical Science Project, National Center for Global Health and Medicine (NCGM), Tokyo, Japan.
• ⁸Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
• ⁹Genome Medical Science Project, National Center for Global Health and Medicine (NCGM), Tokyo, Japan; Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
• ¹⁰Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan, and Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
• ¹¹Department of Medicine, Teikyo University School of Medicine, Tokyo 173-8605, Japan.
• ¹²Division 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 Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China.
• ¹³Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China; Bio-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.
• ¹⁴Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu 210096, China.
• ¹⁵Toronto General Hospital Research Institute, Toronto, Ontario Canada; Department of Medicine, University of Toronto, Toronto, M5S 3H2 Ontario, Canada.
• ¹⁶Mount Sinai Hospital, Lunenfeld Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Canada, M5G 1X5; Department of Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 3H2; Department of Immunology, University of Toronto, Toronto, Ontario, Canada, M5S 3H2; Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 3H2.
• ¹⁷University of California - Davis, Davis, California, USA, 95616.
• ¹⁸Division 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. Electronic address: pietro.invernizzi@unimib.it.

Abstract

Background & aims: Genome-wide association studies (GWAS) in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually-dimorphic complex autoimmune disease.

Methods: We performed a chrX-wide association study (XWAS), including genotype data from five GWAS (from Italy, UK, Canada, China, Japan; 5,244 cases, 11,875 controls).

Results: Single-marker association analyses found ∼100 loci displaying P<5*10-4, with the most significant being a signal within the OTUD5 gene (rs3027490, P=4.80*10-6; OR=1.39 CI=1.028-1.88; Japanese cohort). While the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR=1.17, 95%CI=1.09-1.26; P=9.93*10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asians pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P=6.2*10-9, OR=1.33, CI=1.21-1.46). Indeed, rs7059064 tags a unique LD block including seven genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a super-enhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is predicted to target also FOXP3, the main T regulatory cell lineage-specification factor. Consistently, OTUD5 and FOXP3 RNA levels were upregulated in PBC cases (1.75- and 1.64-fold, respectively).

Conclusion: This work represents the first comprehensive study of the chrX contribution to the genetics of an autoimmune liver disease and revealed a novel PBC-related genome-wide significant locus.