title: Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23.
abstract: The identification of causal genes from genome-wide association studies (GWAS) is the next important step for the translation of genetic findings into biologically meaningful mechanisms of disease and potential therapeutic targets. Using novel chromatin interaction detection techniques and allele specific assays in T and B cell lines, we provide compelling evidence that redefines causal genes at the 6q23 locus, one of the most important loci that confers autoimmunity risk.
  
  
  
  Although the function of disease-associated non-coding single nucleotide polymorphisms (SNPs) at 6q23 is unknown, the association is generally assigned to TNFAIP3, the closest gene. However, the DNA fragment containing the associated SNPs interacts through chromatin looping not only with TNFAIP3, but also with IL20RA, located 680 kb upstream. The risk allele of the most likely causal SNP, rs6927172, is correlated with both a higher frequency of interactions and increased expression of IL20RA, along with a stronger binding of both the NFκB transcription factor and chromatin marks characteristic of active enhancers in T-cells.
  
  
  
  Our results highlight the importance of gene assignment for translating GWAS findings into biologically meaningful mechanisms of disease and potential therapeutic targets; indeed, monoclonal antibody therapy targeting IL-20 is effective in the treatment of rheumatoid arthritis and psoriasis, both with strong GWAS associations to this region.
authors: Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors: Amanda
authors: A
authors: McGovern
authors: Nuclear Dynamics Programme, The Babraham Institute, Cambridge, CB22 3AT, UK.
authors: Stefan
authors: S
authors: Schoenfelder
authors: Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors: Paul
authors: P
authors: Martin
authors: Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors: Jonathan
authors: J
authors: Massey
authors: Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors: Kate
authors: K
authors: Duffus
authors: Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.|NIHR Manchester Musculoskeletal BRU, Manchester Academic Health Sciences Centre, Central Manchester Foundation Trust, Manchester, UK.
authors: Darren
authors: D
authors: Plant
authors: Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors: Annie
authors: A
authors: Yarwood
authors: Institute of Cellular Medicine (Musculoskeletal Research Group), Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors: Arthur G
authors: AG
authors: Pratt
authors: Institute of Cellular Medicine (Musculoskeletal Research Group), Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors: Amy E
authors: AE
authors: Anderson
authors: Institute of Cellular Medicine (Musculoskeletal Research Group), Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors: John D
authors: JD
authors: Isaacs
authors: Institute of Cellular Medicine (Musculoskeletal Research Group), Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors: Julie
authors: J
authors: Diboll
authors: Institute of Cellular Medicine (Musculoskeletal Research Group), Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors: Nishanthi
authors: N
authors: Thalayasingam
authors: Center of Experimental Rheumatology Department of Rheumatology, University Hospital of Zurich, Wagistrasse 14, 8952, Schlieren, Switzerland.
authors: Caroline
authors: C
authors: Ospelt
authors: Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.|NIHR Manchester Musculoskeletal BRU, Manchester Academic Health Sciences Centre, Central Manchester Foundation Trust, Manchester, UK.
authors: Anne
authors: A
authors: Barton
authors: Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.|NIHR Manchester Musculoskeletal BRU, Manchester Academic Health Sciences Centre, Central Manchester Foundation Trust, Manchester, UK.
authors: Jane
authors: J
authors: Worthington
authors: Nuclear Dynamics Programme, The Babraham Institute, Cambridge, CB22 3AT, UK.
authors: Peter
authors: P
authors: Fraser
authors: Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors: Stephen
authors: S
authors: Eyre
authors: Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK. gisela.orozco@manchester.ac.uk.
authors: Gisela
authors: 0000-0002-3479-0448
authors: G
authors: Orozco
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology; D002843:Chromatin / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011565:Psoriasis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D018123:Receptors, Interleukin / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D002843:Chromatin; D018123:Receptors, Interleukin; C492510:interleukin-20 receptor
keywords: Autoimmunity; Capture Hi-C; Causal genes; Functional genomics; Genome-wide association studies (GWAS); Single nucleotide polymorphisms (SNP)