Journal
NATURE GENETICS
Volume 48, Issue 5, Pages 510-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/ng.3528
Keywords
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Categories
Funding
- 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]
- Swedish Research Council [521-2011-2764]
- 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
- 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]
- Swedish Research Council [521-2011-2764]
- 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
- MRC [G0800675] Funding Source: UKRI
- Crohn's and Colitis UK [M11-1] Funding Source: researchfish
- Lundbeck Foundation [R190-2014-3904] Funding Source: researchfish
- Medical Research Council [G0800675] Funding Source: researchfish
- Medical Research Foundation [C0482] Funding Source: researchfish
- NNF Center for Basic Metabolic Research [Pers Group] Funding Source: researchfish
- Novo Nordisk Foundation Center for Protein Research [PI Søren Brunak] Funding Source: researchfish
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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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