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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(1,2) (www.T1DBase.org) revealing major pathways contributing to risk(3), with some loci shared across immune disorders(4–6). In order to make genetic comparisons across autoimmune disorders as informative as possible...

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Detalles Bibliográficos
Autores principales: Onengut-Gumuscu, Suna, Chen, Wei-Min, Burren, Oliver, Cooper, Nick J., Quinlan, Aaron R., Mychaleckyj, Josyf C., Farber, Emily, Bonnie, Jessica K., Szpak, Michal, Schofield, Ellen, Achuthan, Premanand, Guo, Hui, Fortune, Mary D., Stevens, Helen, Walker, Neil M., Ward, Luke D., Kundaje, Anshul, Kellis, Manolis, Daly, Mark J., Barrett, Jeffrey C., Cooper, Jason D., Deloukas, Panos, Todd, John A., Wallace, Chris, Concannon, Patrick, Rich, Stephen S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380767/
https://www.ncbi.nlm.nih.gov/pubmed/25751624
http://dx.doi.org/10.1038/ng.3245
Descripción
Sumario:Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions(1,2) (www.T1DBase.org) revealing major pathways contributing to risk(3), with some loci shared across immune disorders(4–6). In order to make genetic comparisons across autoimmune disorders as informative as possible a dense genotyping array, the ImmunoChip, was developed, from which four novel T1D regions were identified (P < 5 × 10(−8)). A comparative analysis with 15 immune diseases (www.ImmunoBase.org) revealed that T1D is more similar genetically to other autoantibody-positive diseases, most significantly to juvenile idiopathic arthritis and least to ulcerative colitis, and provided support for three additional novel T1D loci. Using a Bayesian approach, we defined credible sets for the T1D SNPs. These T1D 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.