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Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.

Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.

Author information

1
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
2
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
3
Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, UK.
4
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
5
Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
6
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
7
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
8
Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.
9
Division of Rheumatology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
10
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
11
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
12
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
13
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
14
K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
15
Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
16
Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.
17
Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
18
Estonian Genome Center, University of Tartu, Tartu, Estonia.
19
Division of Endocrinology, Boston Children's Hospital, Cambridge, Massachusetts, USA.
20
Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, Massachusetts, USA.
21
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
22
Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
23
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
24
Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands.
25
Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden.
26
BioCruces Health Research Institute and Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
27
Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
28
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
29
Institute of Epidemiology, University Hospital Schleswig-Holstein, Kiel, Germany.
30
PopGen Biobank, University Hospital Schleswig-Holstein, Kiel, Germany.
31
Institute of Human Genetics, University of Bonn, Bonn, Germany.
32
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
33
Department of General Internal Medicine, Universitätsklinikum Schleswig-Holstein Campus Kiel, Kiel, Germany.
34
Department of Dermatology, University Hospital, Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.
35
Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA.
36
Department of Radiology, University of California, San Diego, La Jolla, California, USA.
37
Division of Genetics and Molecular Medicine, King's College London, London, UK.
38
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
39
Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.
40
St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London, London, UK.
41
NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
42
Division of Mental Health and Addiction, Oslo University Hospital, Ullevål, Oslo, Norway.
43
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, California, USA.
44
Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
45
Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
46
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
47
Institute of Health and Biomedical Innovation (IHBI), Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Brisbane, Queensland, Australia.

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.

PMID:
26974007
PMCID:
PMC4848113
DOI:
10.1038/ng.3528
[Indexed for MEDLINE]
Free PMC Article

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