Simultaneous analysis of open chromatin, promoter interactions and gene expression in stimulated T cells implicates GWAS SNPs with causal genes

Genome-wide association studies have identified genetic variation contributing to complex disease risk but assigning causal genes and mechanisms has been more challenging, as disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, the simultaneous correlation of ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data, in the same stimulated T-cells over 24 hours, allowed the assignment of functional enhancers to genes. We show how small magnitude changes in DNA interaction and activity dynamics are correlated with much larger changes to dynamics in gene expression and that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an exemplar T-cell mediated disease, we demonstrate interactions of expression quantitative trait locus SNPs with target genes and confirm assigned genes or show complex interactions for 20% of disease associated loci. Finally, we confirm one of the putative causal genes using CRISPR/Cas9. Overall design: Examine dynamics between open chromatin, chromosome interactions and gene expression in stimulated T cells over 24 hours