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.


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 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.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.

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