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Statistical Colocalization of Genetic Risk Variants for Related Autoimmune Diseases in the Context of Common Controls

View ORCID ProfileMary D Fortune, View ORCID ProfileHui Guo, View ORCID ProfileOliver Burren, View ORCID ProfileEllen Schofield, View ORCID ProfileNeil M Walker, View ORCID ProfileMaria Ban, View ORCID ProfileStephen J Sawcer, View ORCID ProfileJohn Bowes, View ORCID ProfileJane Worthington, View ORCID ProfileAnne Barton, View ORCID ProfileSteve Eyre, View ORCID ProfileJohn A Todd, View ORCID ProfileChris Wallace
doi: https://doi.org/10.1101/020651
Mary D Fortune
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge, CB2 0XY, United Kingdom
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Hui Guo
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge, CB2 0XY, United Kingdom
2Centre for Biostatistics, Institute of Population Health, The University of Manchester, Jean McFarlane Building, Oxford Road, Manchester, M13 9PL, United Kingdom
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Oliver Burren
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge, CB2 0XY, United Kingdom
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Ellen Schofield
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge, CB2 0XY, United Kingdom
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Neil M Walker
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge, CB2 0XY, United Kingdom
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Maria Ban
3University Neurology Unit, Level 5, Block A, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ, United Kingdom
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Stephen J Sawcer
3University Neurology Unit, Level 5, Block A, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ, United Kingdom
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John Bowes
4Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
5National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust, Manchester Academic Health Science, Manchester, United Kingdom
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Jane Worthington
4Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
5National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust, Manchester Academic Health Science, Manchester, United Kingdom
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Anne Barton
4Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
5National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust, Manchester Academic Health Science, Manchester, United Kingdom
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Steve Eyre
4Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
5National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust, Manchester Academic Health Science, Manchester, United Kingdom
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John A Todd
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge, CB2 0XY, United Kingdom
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Chris Wallace
1JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge, CB2 0XY, United Kingdom
6MRC Biostatistics Unit, Cambridge Institute of Public Health, Forvie Site, Robinson Way, Cambridge Biomedical Campus, Cambridge, CB2 0SR, United Kingdom
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Abstract

Identifying whether potential causal variants for related diseases are shared can increase understanding of the shared etiology between diseases. Colocalization methods are designed to disentangle shared and distinct causal variants in regions where two diseases show association, but existing methods are limited by assuming independent datasets. We extended existing methods to allow for the shared control design common in GWAS and applied them to four autoimmune diseases: type 1 diabetes (T1D); rheumatoid arthritis; celiac disease (CEL) and multiple sclerosis (MS). Ninety regions associated with at least one disease. In 22 regions (24%), we identify association to precisely one of our four diseases and can find no published association of any other disease to the same region; some of these may reflect effects mediated by the target of immune attack. Thirty-three regions (37%) were associated with two or more, but in 14 of these there was evidence that causal variants differed between diseases. By leveraging information across datasets, we identified novel disease associations to 12 regions previously associated with one or more of the other three autoimmune disorders. For instance, we link the CEL-associated FASLG region to T1D and identify a single SNP, rs78037977, as a likely causal variant. We also highlight several particularly complex association patterns, including the CD28-CTLA4-ICOS region, in which it appears that three distinct causal variants associate with three diseases in three different patterns. Our results underscore the complexity in genetic variation underlying related but distinct autoimmune diseases and help to approach its dissection.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 08, 2015.
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Statistical Colocalization of Genetic Risk Variants for Related Autoimmune Diseases in the Context of Common Controls
Mary D Fortune, Hui Guo, Oliver Burren, Ellen Schofield, Neil M Walker, Maria Ban, Stephen J Sawcer, John Bowes, Jane Worthington, Anne Barton, Steve Eyre, John A Todd, Chris Wallace
bioRxiv 020651; doi: https://doi.org/10.1101/020651
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Statistical Colocalization of Genetic Risk Variants for Related Autoimmune Diseases in the Context of Common Controls
Mary D Fortune, Hui Guo, Oliver Burren, Ellen Schofield, Neil M Walker, Maria Ban, Stephen J Sawcer, John Bowes, Jane Worthington, Anne Barton, Steve Eyre, John A Todd, Chris Wallace
bioRxiv 020651; doi: https://doi.org/10.1101/020651

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