Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.
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.
1] Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. [2] Department of Medicine, Division of Endocrinology, University of Virginia, Charlottesville, Virginia, USA.
Suna
S
Onengut-Gumuscu
1] Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. [2] Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, USA.
Wei-Min
WM
Chen
Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Oliver
O
Burren
Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Nick J
NJ
Cooper
1] Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. [2] Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, USA.
Aaron R
AR
Quinlan
1] Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. [2] Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, USA.
Josyf C
JC
Mychaleckyj
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
Emily
E
Farber
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
Jessica K
JK
Bonnie
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
Michal
M
Szpak
Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Ellen
E
Schofield
Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Premanand
P
Achuthan
Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Hui
H
Guo
Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Mary D
MD
Fortune
Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Helen
H
Stevens
Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Neil M
NM
Walker
1] Department of Computer Science, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Lucas D
LD
Ward
1] Department of Computer Science, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Genetics, Stanford University, Stanford, California, USA. [4] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Anshul
A
Kundaje
1] Department of Computer Science, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Manolis
M
Kellis
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Mark J
MJ
Daly
Wellcome Trust Sanger Institute, Hinxton, UK.
Jeffrey C
000000021152370X
JC
Barrett
Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Jason D
JD
Cooper
Wellcome Trust Sanger Institute, Hinxton, UK.
Panos
000000019251070X
P
Deloukas
Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
John A
JA
Todd
1] Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. [2] Medical Research Council (MRC) Biostatistics Unit, Institute of Public Health, University Forvie Site, Cambridge, UK.
Chris
0000000197551703
C
Wallace
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
Patrick
0000000258011859
P
Concannon
1] Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. [2] Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, USA.
Stephen S
SS
Rich
D001323:Autoantibodies / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis / Q000379:methods; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D004742:Enhancer Elements, Genetic; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D020641:Polymorphism, Single Nucleotide
D001323:Autoantibodies