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Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
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.
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2016 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 5, p. 510-518Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
New York, USA: Nature Publishing Group, 2016. Vol. 48, no 5, p. 510-518
National Category
Medical Genetics
Research subject
Genetics
Identifiers
URN: urn:nbn:se:oru:diva-49331DOI: 10.1038/ng.3528ISI: 000374834100010PubMedID: 26974007Scopus ID: 2-s2.0-84964772502OAI: oai:DiVA.org:oru-49331DiVA, id: diva2:912038
Funder
Swedish Research Council, 521-2011-2764
Note

Funding Agencies:

German Federal Ministry of Education and Research (BMBF) 01ZX1306A

Estonian Research Council IUT20-60

Center of Excellence in Genomics (EXCEGEN)

University of Tartu (SP1GVARENG)

UK Department of Health via National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre awards to Guy's and St Thomas' National Health Service (NHS) Foundation Trust

King's College London

University of Cambridge

German Federal Ministry of Education and Research (BMBF), within the context of National Genome Research Network 2 (NGFN-2)

National Genome Research Network plus (NGFNplus)

Integrated Genome Research Network (IG) MooDS 01GS08144  01GS08147

Netherlands Organization for Scientific Research (NWO) 016.136.308

US NIH 1R01AR063759  5U01GM092691-05  1UH2AR067677-01  U19AI111224-01  1R01DK084960-05

Doris Duke Charitable Foundation 2013097

Novo Nordisk Foundation NNF14CC0001

H2020 project MedBioinformatics 634143

Norwegian PSC Research Center

Available from: 2016-03-15 Created: 2016-03-15 Last updated: 2018-09-14Bibliographically approved

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Halfvarson, Jonas

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