title: Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes.
abstract: The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1-5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom.
authors: Natalie J
authors: NJ
authors: Prescott
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom; Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.
authors: Benjamin
authors: B
authors: Lehne
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom.
authors: Kristina
authors: K
authors: Stone
authors: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors: James C
authors: JC
authors: Lee
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom.
authors: Kirstin
authors: K
authors: Taylor
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors: Jo
authors: J
authors: Knight
authors: NIHR GSTFT/KCL Comprehensive Biomedical Research Centre Genomics Core Facility, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
authors: Efterpi
authors: E
authors: Papouli
authors: NIHR GSTFT/KCL Comprehensive Biomedical Research Centre Genomics Core Facility, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
authors: Muddassar M
authors: MM
authors: Mirza
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom.
authors: Michael A
authors: MA
authors: Simpson
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom.
authors: Sarah L
authors: SL
authors: Spain
authors: Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, United Kingdom.
authors: Grace
authors: G
authors: Lu
authors: Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, United Kingdom.
authors: Franca
authors: F
authors: Fraternali
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors: Suzannah J
authors: SJ
authors: Bumpstead
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors: Emma
authors: E
authors: Gray
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom.
authors: Ariella
authors: A
authors: Amar
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom.
authors: Hannah
authors: H
authors: Bye
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom.
authors: Peter
authors: P
authors: Green
authors: Department of Gastroenterology, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom.
authors: Guy
authors: G
authors: Chung-Faye
authors: Department of Gastroenterology, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom.
authors: Bu'Hussain
authors: B
authors: Hayee
authors: Gastroenterology and Hepatology, St George's Healthcare NHS Trust, Tooting, London, United Kingdom.
authors: Richard
authors: R
authors: Pollok
authors: Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors: Jack
authors: J
authors: Satsangi
authors: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors: Miles
authors: M
authors: Parkes
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors: Jeffrey C
authors: JC
authors: Barrett
authors: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors: John C
authors: JC
authors: Mansfield
authors: Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, Department of Gastroenterology, London, United Kingdom.
authors: Jeremy
authors: J
authors: Sanderson
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom.
authors: Cathryn M
authors: CM
authors: Lewis
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom.
authors: Michael E
authors: ME
authors: Weale
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom.
authors: Thomas
authors: T
authors: Schlitt
authors: Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom; Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa.
authors: Christopher G
authors: CG
authors: Mathew
mesh_terms: D000071797:Butyrophilins; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: C408263:BTNL2 protein, human; D000071797:Butyrophilins; D006680:HLA Antigens; D008562:Membrane Glycoproteins