Citation: Gastroenterology. 2021, S0016-5085(21), 00466-2. Online ahead of print
Author: Rosanna Asselta, Elvezia Maria Paraboschi, Alessio Gerussi, Heather J Cordell, George F Mells, Richard N Sandford, David E Jones, Minoru Nakamura, Kazuko Ueno, Yuki Hitomi, Minae Kawashima, Nao Nishida, Katsushi Tokunaga, Masao Nagasaki, Atsushi Tanaka, Ruqi Tang, Zhiqiang Li, Yongyong Shi, Xiangdong Liu, Ma Xiong, Gideon Hirschfield, Katherine A Siminovitch, Canadian-US PBC Consortium; Italian PBC Genetics Study Group; UK-PBC Consortium; Japan PBC-GWAS Consortium; Marco Carbone, Giulia Cardamone, Stefano Duga, M Eric Gershwin, Michael F Seldin, Pietro Invernizzi
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.
Keywords: Meta-analysis; Superenhancer; X-Wide Association Study.
Friday 9 April 2021
WUTH publication: X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis
