title: Functional implications of disease-specific variants in loci jointly associated with coeliac disease and rheumatoid arthritis.
abstract: Hundreds of genomic loci have been associated with a significant number of immune-mediated diseases, and a large proportion of these associated loci are shared among traits. Both the molecular mechanisms by which these loci confer disease susceptibility and the extent to which shared loci are implicated in a common pathogenesis are unknown. We therefore sought to dissect the functional components at loci shared between two autoimmune diseases: coeliac disease (CeD) and rheumatoid arthritis (RA). We used a cohort of 12 381 CeD cases and 7827 controls, and another cohort of 13 819 RA cases and 12 897 controls, all genotyped with the Immunochip platform. In the joint analysis, we replicated 19 previously identified loci shared by CeD and RA and discovered five new non-HLA loci shared by CeD and RA. Our fine-mapping results indicate that in nine of 24 shared loci the associated variants are distinct in the two diseases. Using cell-type-specific histone markers, we observed that loci which pointed to the same variants in both diseases were enriched for marks of promoters active in CD14+ and CD34+ immune cells (P < 0.001), while loci pointing to distinct variants in one of the two diseases showed enrichment for marks of more specialized cell types, like CD4+ regulatory T cells in CeD (P < 0.0001) compared with Th17 and CD15+ in RA (P = 0.0029).
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Javier
authors.initials: J
authors.lastname: Gutierrez-Achury
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Maria Magdalena
authors.initials: MM
authors.lastname: Zorro
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Isis
authors.initials: I
authors.lastname: Ricaño-Ponce
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Daria V
authors.initials: DV
authors.lastname: Zhernakova
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA, Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA, USA and.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Diogo
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands, a.zhernakova@umcg.nl.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology; D002874:Chromosome Mapping; D015331:Cohort Studies; D056726:Genetic Association Studies; D006801:Humans; D040641:Quantitative Trait Loci