title: Identifying Causal Genes at the Multiple Sclerosis Associated Region 6q23 Using Capture Hi-C.
abstract: BACKGROUND
  The chromosomal region 6q23 has been found to be associated with multiple sclerosis (MS) predisposition through genome wide association studies (GWAS). There are four independent single nucleotide polymorphisms (SNPs) associated with MS in this region, which spans around 2.5 Mb. Most GWAS variants associated with complex traits, including these four MS associated SNPs, are non-coding and their function is currently unknown. However, GWAS variants have been found to be enriched in enhancers and there is evidence that they may be involved in transcriptional regulation of their distant target genes through long range chromatin looping.
  
  
  OBJECTIVE
  The aim of this work is to identify causal disease genes in the 6q23 locus by studying long range chromatin interactions, using the recently developed Capture Hi-C method in human T and B-cell lines. Interactions involving four independent associations unique to MS, tagged by rs11154801, rs17066096, rs7769192 and rs67297943 were analysed using Capture Hi-C Analysis of Genomic Organisation (CHiCAGO).
  
  
  RESULTS
  We found that the pattern of chromatin looping interactions in the MS 6q23 associated region is complex. Interactions cluster in two regions, the first involving the rs11154801 region and a second containing the rs17066096, rs7769192 and rs67297943 SNPs. Firstly, SNPs located within the AHI1 gene, tagged by rs11154801, are correlated with expression of AHI1 and interact with its promoter. These SNPs also interact with other potential candidate genes such as SGK1 and BCLAF1. Secondly, the rs17066096, rs7769192 and rs67297943 SNPs interact with each other and with immune-related genes such as IL20RA, IL22RA2, IFNGR1 and TNFAIP3. Finally, the above-mentioned regions interact with each other and therefore, may co-regulate these target genes.
  
  
  CONCLUSIONS
  These results suggest that the four 6q23 variants, independently associated with MS, are involved in the regulation of several genes, including immune genes. These findings could help understand mechanisms of disease and suggest potential novel therapeutic targets.
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Siences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, United Kingdom.
authors.forename: Paul
authors.identifier: http://orcid.org/0000-0002-1016-6851
authors.initials: P
authors.lastname: Martin
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Siences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, United Kingdom.
authors.forename: Amanda
authors.identifier: http://orcid.org/0000-0001-7727-3283
authors.initials: A
authors.lastname: McGovern
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Siences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, United Kingdom.
authors.forename: Jonathan
authors.identifier: http://orcid.org/0000-0002-4576-1124
authors.initials: J
authors.lastname: Massey
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Cambridge CB22 3AT, United Kingdom.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schoenfelder
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Siences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, United Kingdom.
authors.forename: Kate
authors.identifier: http://orcid.org/0000-0002-8925-1863
authors.initials: K
authors.lastname: Duffus
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Siences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, United Kingdom.
authors.forename: Annie
authors.identifier: http://orcid.org/0000-0001-5026-9815
authors.initials: A
authors.lastname: Yarwood
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Siences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, United Kingdom.|NIHR Manchester Musculoskeletal BRU, Manchester Academic Health Sciences Centre, Central Manchester Foundation Trust, Manchester, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Siences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, United Kingdom.|NIHR Manchester Musculoskeletal BRU, Manchester Academic Health Sciences Centre, Central Manchester Foundation Trust, Manchester, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Cambridge CB22 3AT, United Kingdom.
authors.forename: Peter
authors.identifier: http://orcid.org/0000-0002-0041-1227
authors.initials: P
authors.lastname: Fraser
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Siences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Eyre
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Siences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, United Kingdom.
authors.forename: Gisela
authors.initials: G
authors.lastname: Orozco
mesh_terms: D002460:Cell Line; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6; D019295:Computational Biology / Q000379:methods; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D023281:Genomics / Q000379:methods; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci