TY - JOUR
T1 - Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers
AU - Onengut-Gumuscu, Suna
AU - Chen, Wei Min
AU - Burren, Oliver
AU - Cooper, Nick J.
AU - Quinlan, Aaron R.
AU - Mychaleckyj, Josyf C.
AU - Farber, Emily
AU - Bonnie, Jessica K.
AU - Szpak, Michal
AU - Schofield, Ellen
AU - Achuthan, Premanand
AU - Guo, Hui
AU - Fortune, Mary D.
AU - Stevens, Helen
AU - Walker, Neil M.
AU - Ward, Lucas D.
AU - Kundaje, Anshul
AU - Kellis, Manolis
AU - Daly, Mark J.
AU - Barrett, Jeffrey C.
AU - Cooper, Jason D.
AU - Deloukas, Panos
AU - Todd, John A.
AU - Wallace, Chris
AU - Concannon, Patrick
AU - Rich, Stephen S.
AU - Baskerville, Tracey
AU - Bautista, Nines
AU - Bhatia, Eesh
AU - Bhatia, Vijayalakshmi
AU - Hasan, Kamaruzaman Bin
AU - Bonnici, Francois
AU - Brodnicki, Thomas
AU - Browning, Brian
AU - Cameron, Fergus
AU - Chaichanwatanakul, Katharee
AU - Cheung, Pik To
AU - Colman, Peter
AU - Cotterill, Andrew
AU - Couper, Jenny
AU - Crock, Patricia
AU - Cutfield, Ric
AU - Davis, Tim
AU - Dixon, Paul
AU - Donaghue, Kim
AU - Dowling, Katrina
AU - Drury, Paul
AU - Dye, Sarah
AU - Gellert, Shane
AU - Ghani, Rohana Abdul
AU - Type 1 Diabet Genetics Consortium
AU - Dzīvīte-Krišāne, Iveta
N1 - Funding Information:
This research uses resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD) and JDRF and supported by grant U01 DK062418 from the US National Institutes of Health. Further support was provided by grants from the NIDDK (DK046635 and DK085678) to P.C. and by a joint JDRF and Wellcome Trust grant (WT061858/09115) to the Diabetes and Inflammation Laboratory at Cambridge University, which also received support from the NIHR Cambridge Biomedical Research Centre. ImmunoBase receives support from Eli Lilly and Company. C.W. and H.G. are funded by the Wellcome Trust (089989). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140).
Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/4/28
Y1 - 2015/4/28
N2 - Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10-8). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34 + stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.
AB - Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10-8). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34 + stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.
UR - http://www.scopus.com/inward/record.url?scp=84930408328&partnerID=8YFLogxK
U2 - 10.1038/ng.3245
DO - 10.1038/ng.3245
M3 - Article
C2 - 25751624
AN - SCOPUS:84930408328
SN - 1061-4036
VL - 47
SP - 381
EP - 386
JO - Nature Genetics
JF - Nature Genetics
IS - 4
ER -