title: Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.
abstract: We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Ellinghaus
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Jostins
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Sarah L
authors.identifier: 0000-0002-7591-8364
authors.initials: SL
authors.lastname: Spain
authors.affiliation: Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Cortes
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Bethune
authors.affiliation: Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Buhm
authors.initials: B
authors.lastname: Han
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Yu Rang
authors.initials: YR
authors.lastname: Park
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Rheumatology, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: 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.forename: Jennie G
authors.initials: JG
authors.lastname: Pouget
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Matthias
authors.identifier: 0000-0002-5956-3006
authors.initials: M
authors.lastname: Hübenthal
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.
authors.forename: Trine
authors.initials: T
authors.lastname: Folseraas
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.|Division of Endocrinology, Boston Children's Hospital, Cambridge, Massachusetts, USA.|Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, Massachusetts, USA.
authors.forename: Tonu
authors.identifier: 0000-0003-1982-6569
authors.initials: T
authors.lastname: Esko
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Rheumatology, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Harm-Jan
authors.identifier: 0000-0001-7038-567X
authors.initials: HJ
authors.lastname: Westra
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Lude
authors.identifier: 0000-0002-5159-8802
authors.initials: L
authors.lastname: Franke
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, Massachusetts, USA.|Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.|Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Tune H
authors.initials: TH
authors.lastname: Pers
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Valerie
authors.initials: V
authors.lastname: Collij
authors.affiliation: Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden.|BioCruces Health Research Institute and Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
authors.affiliation: Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
authors.forename: Jonas
authors.identifier: 0000-0003-0122-7234
authors.initials: J
authors.lastname: Halfvarson
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders Boeck
authors.initials: AB
authors.lastname: Jensen
authors.affiliation: Institute of Epidemiology, University Hospital Schleswig-Holstein, Kiel, Germany.|PopGen Biobank, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Forstner
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.|Department of General Internal Medicine, Universitätsklinikum Schleswig-Holstein Campus Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Department of Dermatology, University Hospital, Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mrowietz
authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Juran
authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA.
authors.forename: Konstantinos N
authors.initials: KN
authors.lastname: Lazaridis
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.|Department of Radiology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.affiliation: Department of Dermatology, University Hospital, Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Weidinger
authors.affiliation: Department of Dermatology, University Hospital, Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Weichenthal
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Eva
authors.identifier: 0000-0003-2914-3382
authors.initials: E
authors.lastname: Ellinghaus
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.|Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: Jonathan N W N
authors.initials: JN
authors.lastname: Barker
authors.affiliation: NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Division of Mental Health and Addiction, Oslo University Hospital, Ullevål, Oslo, Norway.
authors.forename: Ole A
authors.identifier: 0000-0002-4461-3568
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, California, USA.|Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Dermot P
authors.initials: DP
authors.lastname: McGovern
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Jeffrey C
authors.identifier: 0000-0002-1152-370X
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Miles
authors.initials: M
authors.lastname: Parkes
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.|Institute of Health and Biomedical Innovation (IHBI), Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
mesh_terms: D001499:Bayes Theorem; D015209:Cholangitis, Sclerosing / Q000235:genetics*; D002908:Chronic Disease; D003093:Colitis, Ulcerative / Q000235:genetics*; D015897:Comorbidity; D003424:Crohn Disease / Q000235:genetics*; D018740:Genetic Heterogeneity; D058685:Genetic Pleiotropy; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D011565:Psoriasis / Q000235:genetics*; D040641:Quantitative Trait Loci; D013167:Spondylitis, Ankylosing / Q000235:genetics*