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Nature Research, Nature Genetics, 7(47), p. 839-846, 2015

DOI: 10.1038/ng.3330

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

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

This is the author accepted manuscript. The final version is available at http://www.nature.com/ng/journal/v47/n7/full/ng.3330.html. ; Determining whether potential causal variants for related diseases are shared can identify overlapping etiologies of multifactorial disorders. Colocalization methods disentangle shared and distinct causal variants. However, existing approaches require independent data sets. Here we extend two colocalization methods to allow for the shared-control design commonly used in comparison of genome-wide association study results across diseases. Our analysis of four autoimmune diseases?type 1 diabetes (T1D), rheumatoid arthritis, celiac disease and multiple sclerosis?identified 90 regions that were associated with at least one disease, 33 (37%) of which were associated with 2 or more disorders. Nevertheless, for 14 of these 33 shared regions, there was evidence that the causal variants differed. We identified new disease associations in 11 regions previously associated with one or more of the other 3 disorders. Four of eight T1D-specific regions contained known type 2 diabetes (T2D) candidate genes (COBL, GLIS3, RNLS and BCAR1), suggesting a shared cellular etiology. ; MF is funded by the Wellcome Trust (099772). CW and HG are funded by the Wellcome Trust (089989). This work was funded by the JDRF (9?2011?253), the Wellcome Trust (091157) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). ImmunoBase.org is supported by Eli Lilly and Company. We thank the UK Medical Research Council and Wellcome Trust for funding the collection of DNA for the British 1958 Birth Cohort (MRC grant G0000934, WT grant 068545/Z/02). DNA control samples were prepared and provided by S. Ring, R. Jones, M. Pembrey, W. McArdle, D. Strachan and P. Burton. Biotec Cluster M4, the Fidelity Biosciences Research Initiative, Research Foundation Flanders, Research Fund KU Leuven, the Belgian Charcot Foundation, Gemeinntzige Hertie Stiftung, University Zurich, the Danish MS Society, the Danish Council for Strategic Research, the Academy of Finland, the Sigrid Juselius Foundation, Helsinki University, the Italian MS Foundation, Fondazione Cariplo, the Italian Ministry of University and Research, the Torino Savings Bank Foundation, the Italian Ministry of Health, the Italian Institute of Experimental Neurology, the MS Association of Oslo, the Norwegian Research Council, the South?Eastern Norwegian Health Authorities, the Australian National Health and Medical Research Council, the Dutch MS Foundation and Kaiser Permanente. Marina Evangelou is thanked for motivating the investigation of the FASLG association.