Year: 2017
Type: preprint
Abstract: Background Autoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4 + T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes. Results Within four hours, activation of CD4 + T cells invokes changes in histone modifications and enhancer RNA transcription that correspond to altered expression of the interacting genes identified by promoter capture Hi-C. By integrating promoter capture Hi-C data with genetic associations for five autoimmune diseases we prioritised 245 candidate genes with a median distance from peak signal to prioritised gene of 153 kb. Just under half (108/245) prioritised genes related to activation-sensitive interactions. This included IL2RA , where allele-specific expression analyses were consistent with its interaction-mediated regulation, illustrating the utility of the approach. Conclusions Our systematic experimental framework offers an alternative approach to candidate causal gene identification for variants with cell state-specific functional effects, with achievable sample sizes.
DOI: 10.1101/100958
Authors: Oliver S Burren, Arcadio Rubio García, Biola-Maria Javierre, Daniel B Rainbow, Jonathan Cairns, Nicholas J Cooper, John J Lambourne, Ellen Schofield, Xaquin Castro Dopico, Ricardo C Ferreira, Richard Coulson, Frances Burden, Sophia P Rowlston, Kate Downes, Steven W Wingett, Mattia Frontini, Willem H Ouwehand, Peter Fraser, Mikhail Spivakov, John A Todd, Linda S Wicker, Antony J Cutler, Chris Wallace
Institutions: University of Cambridge, National Institute for Health and Care Research, Addenbrooke's Hospital, NIHR Cambridge Biomedical Research Centre, Wellcome Trust, Centre for Human Genetics, University of Oxford, NIHR Oxford Biomedical Research Centre, Babraham Institute, National Health Service, British Heart Foundation, Wellcome Sanger Institute, MRC Biostatistics Unit
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: NHS Blood and Transplant, Wellcome Trust, National Institute for Health and Care Research, European Commission, Directorate for Biological Sciences, NIHR BioResource, Medical Research Council, Cambridge Institute for Medical Research, University of Cambridge, NIHR Cambridge Biomedical Research Centre, National Human Genome Research Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Child Health and Human Development
Awards: Linking Regulatory Elements Harboring Common Disease-Associated Variants to Their Target Genes, G119964413, Novel immunotherapies for type 1 diabetes, Partitioning autoimmune diseases on their molecular basis., G2473632591, G2473961061, Diabetes and Inflammation Laboratory., G3202681502, G3207356259, G3673804865, G393177772, G4140938724, Partitioning autoimmune diseases on their molecular basis., G4273598029, Cellular Medicine at the Cambridge Institute for Medical Research., G5702163051, Type 1 Diabetes Genetics Consortium, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G7355666782, Cellular Medicine at the Cambridge Institute for Medical Research., Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G8975541179, G9000255165, Genes and Pathways in Type 1 Diabetes.
OpenAlex ID: W2571755945