Multi-omics analysis in primary T cells elucidates mechanisms behind disease associated genetic loci

Genome-wide association studies (GWAS) have revealed the genetic basis behind many diseases, but interpreting them is challenging as most loci affect regulatory regions. Chromatin conformation is crucial in gene regulation, often used to link potential target genes to regulatory regions. However, past studies used small sample sizes and immortalized cell lines instead of primary cells.

Here, we present the largest dataset of chromatin conformation with matching gene expression and chromatin accessibility from primary CD4+ and CD8+ T cells, isolated from psoriatic arthritis patients and healthy controls. We generated 108 Hi-C libraries (49 billion reads), 128 RNA-seq libraries, and 126 ATAC-seq libraries. These data enhance our understanding of how GWAS variants affect gene regulation, showing how genetic variation alters chromatin accessibility and structure in primary cells at an unprecedented scale. We refine the mapping of GWAS loci to regulatory elements, such as CTCF binding sites and enhancers, aiding gene assignment. We identify BCL2L11 as the probable causal gene within the rheumatoid arthritis (RA) locus rs13396472, despite the GWAS variants being intronic to ACOXL, and uncover mechanisms involving SESN3 dysregulation in the RA locus rs4409785.

Given these genes' significant role in T cell development, our work deepens the understanding of autoimmune disease pathogenesis, suggesting potential treatment targets. Additionally, our dataset is a valuable resource for investigating immune-mediated diseases and gene regulatory mechanisms.