Faculty Collaboration Database

Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet 2015 Apr;47(4):381-6

Date

03/10/2015

Pubmed ID

25751624

Pubmed Central ID

PMC4380767

DOI

10.1038/ng.3245

Scopus ID

2-s2.0-84930408328 (requires institutional sign-in at Scopus site)   471 Citations

Abstract

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.

Author List

Onengut-Gumuscu S, Chen WM, Burren O, Cooper NJ, Quinlan AR, Mychaleckyj JC, Farber E, Bonnie JK, Szpak M, Schofield E, Achuthan P, Guo H, Fortune MD, Stevens H, Walker NM, Ward LD, Kundaje A, Kellis M, Daly MJ, Barrett JC, Cooper JD, Deloukas P, Type 1 Diabetes Genetics Consortium, Todd JA, Wallace C, Concannon P, Rich SS

Author

Rosanna V. Fiallo-Scharer MD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Autoantibodies
Autoimmunity
Case-Control Studies
Chromosome Mapping
DNA Mutational Analysis
Diabetes Mellitus, Type 1
Enhancer Elements, Genetic
Female
Genetic Association Studies
Genetic Loci
Genetic Predisposition to Disease
Humans
Lymphocytes
Male
Polymorphism, Single Nucleotide