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Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers

Onegut-Gumuscu, S; Chen, W-M; Burren, O; Cooper, N J; Quinlan, A R; Mychaleckyj, J C; Farber, E; Bonnie, J K; Szpak, M; Schofield, E; Achuthan, P; Guo, H; Fortune, M D; Stevens, H; Walker, N M; Ward, L D; Kundaje, A; Kellis, M; Daly, M J; Barrett, J C; Cooper, J D; Deloukas, P; Type 1 Diabetes Genetics Consortium; Todd, J A; Wallace, C; Concannon, P; Rich, S S

Authors

S Onegut-Gumuscu

W-M Chen

O Burren

N J Cooper

A R Quinlan

J C Mychaleckyj

E Farber

J K Bonnie

M Szpak

E Schofield

P Achuthan

H Guo

M D Fortune

H Stevens

N M Walker

L D Ward

A Kundaje

M Kellis

M J Daly

J C Barrett

J D Cooper

P Deloukas

Type 1 Diabetes Genetics Consortium

J A Todd

C Wallace

P Concannon

S S Rich



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.

Citation

Onegut-Gumuscu, S., Chen, W., Burren, O., Cooper, N. J., Quinlan, A. R., Mychaleckyj, J. C., …Rich, S. S. (2015). Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nature Genetics, 47(4), 381-6. https://doi.org/10.1038/ng.3245

Journal Article Type Letter
Acceptance Date Feb 13, 2015
Publication Date Mar 9, 2015
Deposit Date Jun 4, 2018
Journal Nature Genetics
Print ISSN 1061-4036
Publisher Nature Research
Peer Reviewed Peer Reviewed
Volume 47
Issue 4
Pages 381-6
DOI https://doi.org/10.1038/ng.3245
Public URL https://rvc-repository.worktribe.com/output/1401617

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