IRCCS Humanitas Research Hospital & Humanitas University
Published December 23, 2021 | Version v1
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Link to dataset related to article "X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis"

Authors/Creators

  • 1. Department of Biomedical Sciences, Humanitas University, Milan, Italy; IRCCS Humanitas Research Hospital, Milan, Italy
  • 2. Division 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, San Gerardo Hospital, Monza, Italy
  • 3. Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, United Kingdom
  • 4. Academic Department of Medical Genetics, Cambridge University, Cambridge, United Kingdom
  • 5. Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
  • 6. Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Nagasaki, Japan; Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Nagasaki, Japan
  • 7. Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
  • 8. Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  • 9. Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan; Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  • 10. Human 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
  • 11. Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
  • 12. Division 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, Shanghai, China
  • 13. Affiliated 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
  • 14. Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu, China
  • 15. Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 16. Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Mount Sinai Hospital, Lunenfeld Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
  • 17. Canadian-US PBC Consortium
  • 18. Italian PBC Genetics Study Group
  • 19. UK-PBC Consortium
  • 20. Japan PBC-GWAS Consortium
  • 21. University of California-Davis, Davis, California

Description

Link to dataset related to article "X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis"

Abstract

Background & aims: Genome-wide association studies 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, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals).

Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although 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 Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively).

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

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Additional details

Related works

Is supplement to
10.1053/j.gastro.2021.02.061 (DOI)
33675743 (PMID)