X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Gastroenterology. 2021 Jun;160(7):2483-2495.e26. doi: 10.1053/j.gastro.2021.02.061. Epub 2021 Mar 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Asian People / genetics
  • Carrier Proteins / genetics
  • Cell Lineage / genetics
  • Chromosomes, Human, X / genetics*
  • DNA-Binding Proteins / genetics
  • Endopeptidases / genetics
  • Female
  • Forkhead Transcription Factors / genetics
  • Genetic Loci / genetics
  • Genetic Predisposition to Disease / ethnology
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium / genetics
  • Liver Cirrhosis, Biliary / genetics*
  • Male
  • Mitochondrial Precursor Protein Import Complex Proteins / genetics
  • Monosaccharide Transport Proteins / genetics
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Protein Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins / genetics
  • Shal Potassium Channels / genetics
  • White People / genetics

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • GRIPAP1 protein, human
  • KCND1 protein, human
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Monosaccharide Transport Proteins
  • PIM2 protein, human
  • PQBP1 protein, human
  • Proto-Oncogene Proteins
  • Shal Potassium Channels
  • TIMM17B protein, human
  • UDP-galactose translocator
  • Protein Serine-Threonine Kinases
  • Endopeptidases
  • OTUD5 protein, human