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Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci
Open accessAbstract
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.
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Metadata
- Authors
- The International IBD Genetics Consortium (IIBDGC), Ellinghaus, D., International Genetics of Ankylosing Spondylitis Consortium (IGAS), International PSC Study Group (IPSCSG), Genetic Analysis of Psoriasis Consortium (GAPC), Psoriasis Association Genetics Extension (PAGE), Jostins, L., Spain, S. L., Cortes, A., Bethune, J., Han, B., Park, Y. R., Raychaudhuri, S., Pouget, J. G., Hübenthal, M., Folseraas, T., Wang, Y., Esko, T., Metspalu, A., Westra, H.-J., Franke, L., Pers, T. H., Weersma, R. K., Collij, V., D'Amato, M., Halfvarson, J., Jensen, A. B., Lieb, W., Degenhardt, F., Forstner, A. J., Hofmann, A., Schreiber, S., Mrowietz, U., Juran, B. D., Lazaridis, K. N., Brunak, S., Dale, A. M., Trembath, R. C., Weidinger, S., Weichenthal, M., Ellinghaus, E., Elder, J. T., Barker, J. N. W. N., Andreassen, O. A., McGovern, D. P., Karlsen, T. H., Barrett, J. C., Parkes, M., Brown, M. A., & Franke, A.
- Affiliations
- Christian-Albrechts-Universität zu Kiel (DE)
- Wellcome Sanger Institute (GB)
- Centre for Human Genetics (GB)
- Asan Medical Center (KR)
- Broad Institute (US)
- Centre for Addiction and Mental Health (CA)
- Oslo University Hospital (NO)
- Boston Children's Hospital (US)
- Brigham and Women's Hospital (US)
- Statens Serum Institut (DK)
- University Medical Center Groningen (NL)
- Ikerbasque (ES)
- University of Copenhagen (DK)
- University of Bonn (DE)
- Mayo Clinic (US)
- King's College London (GB)
- University of Michigan (US)
- University of Cambridge (GB)
- Translational Research Institute (AU)
- Corresponding author
- Ellinghaus, David
- ORCID
- Ellinghaus, David
- Spain, Sarah L
- Bethune, Jörn
- Han, Buhm
- Park, Yu Rang
- Raychaudhuri, Soumya
- Pouget, Jennie G
- Hübenthal, Matthias
- Folseraas, Trine
- Wang, Yunpeng
- Esko, Tonu
- Metspalu, Andres
- Westra, Harm-Jan
- Franke, Lude
- Pers, Tune H
- Weersma, Rinse K
- Collij, Valerie
- Halfvarson, Jonas
- Jensen, Anders Boeck
- Lieb, Wolfgang
- Degenhardt, Franziska
- Forstner, Andreas J
- Schreiber, Stefan
- Mrowietz, Ulrich
- Lazaridis, Konstantinos N
- Brunak, Søren
- Dale, Anders M
- Trembath, Richard C
- Weidinger, Stephan
- Weichenthal, Michael
- Ellinghaus, Eva
- Andreassen, Ole A
- McGovern, Dermot P
- Karlsen, Tom H
- Barrett, Jeffrey C
- Parkes, Miles
- Brown, Matthew A
- Venue
- Nature Genetics
- Published
- 2016-03-14
- Volume
- 48
- Issue
- 5
- Pages
- 510-518
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4848113
- OpenAlex
- W2297994856
- Semantic Scholar
- 372a076554a5ec1f9e595ef356670468d66cfa6a
- Cited by
- 751
- References
- 55
- Citations by year
- 2026: 45 · 2025: 52 · 2024: 69 · 2023: 81 · 2022: 99 · 2021: 95 · 2020: 82 · 2019: 80 · 2018: 56 · 2017: 69 · 2016: 22
- FWCI
- 61.13
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- UWA Profiles and Research Repository (UWA) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- QUT ePrints (Queensland University of Technology) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- National Institute for Health and Care Research
- King's College London
- Deutsche Forschungsgemeinschaft (01ZX1306A)
- Eesti Teadusagentuur (IUT20-60)
- Bundesministerium für Bildung und Forschung (01GS08147, 01ZX1306A, 01GS08144)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (016.136.308)
- Crohn's and Colitis UK (M11-1)
- Lundbeckfonden (R190 2014-3904)
- Novo Nordisk (NNF14CC0001)
- Vetenskapsrådet (521‐2011‐2764)
- Tartu Ülikool (SP1GVARENG)
- Novo Nordisk Fonden (NNF 14CC0001)
- Exzellenzclusters Entzündungsforschung
- National Institutes of Health (5r01ar063759-07, H2020, 1R01‐AR‐063759, U19-AI111224-01, AI111224)
- Horizon 2020 Framework Programme (634143)
- National Institute of General Medical Sciences (U01GM092691)
- National Institute of Allergy and Infectious Diseases (U19AI111224)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK084960)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (UH2AR067677, R01AR050511, R01AR042742, R01AR065183, R01AR063611, R01-AR063759)
- National Center for Research Resources (M01RR000042)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Health Sciences › Medicine › Rheumatology › Spondyloarthritis Studies and Treatments
- Keywords
- chronic inflammatory diseases, pleiotropy, ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis, inflammatory bowel disease, genetic susceptibility loci, comorbidities, gene expression, immune disorders
- MeSH terms
- Bayes Theorem, Chronic Disease, Colitis, Ulcerative, Crohn Disease, Genotype, Humans, Inflammation, Psoriasis, Spondylitis, Ankylosing, Genetic Variation, Cholangitis, Sclerosing, Comorbidity, Genetic Heterogeneity, Quantitative Trait Loci, Genome-Wide Association Study, Genetic Pleiotropy
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