Abstract

Through genome wide association studies (GWAS) over 320 distinct loci have been robustly associated with autoimmune disease susceptibility. Candidate causal variants are enriched in regulatory regions, but connecting these regulatory variants to target genes within relevant tissue contexts has proved challenging. In this talk I will describe one such approach for linking variants with the genes they regulate by mapping physical chromosome contacts, through the use of promoter capture Hi-C (PCHi-C). By the application of novel statistical methods which combine GWAS datasets with chromatin contact maps for 17 primary human blood cells, we were able to prioritise putative disease mechanisms for functional validation. To support our approach, we found evidence for allelically imbalanced transcription of IL2RA within CD4 + T cells of individuals heterozygous for PCHi-C linked autoimmune-associated variants. This allelic imbalance is specific to non-activated cells, reflecting the predicted effect of context-sensitive chromatin interactions.