Chromosome contacts in activated T cells identify autoimmune disease candidate genes.
Burren OS., Rubio García A., Javierre BM., Rainbow DB., Cairns J., Cooper NJ., Lambourne JJ., Schofield E., Castro Dopico X., Ferreira RC., Coulson R., Burden F., Rowlston SP., Downes K., Wingett SW., Frontini M., Ouwehand WH., Fraser P., Spivakov M., Todd JA., Wicker LS., Cutler AJ., Wallace C.
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.Within 4 h, 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.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.