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

Abstract

Abstract In this study, we present the most extensive dataset of chromatin conformation with matching gene expression and chromatin accessibility from primary T cells to date. We use this data to enhance our understanding of the mechanisms by which GWAS variants impact gene regulation, revealing how genetic variation alters chromatin accessibility and structure in primary cells at an unprecedented scale. We refine the mapping of GWAS loci to implicated regulatory elements, such as CTCF binding sites and other enhancer elements, aiding gene assignment. Importantly, we uncover BCL2L11 as the probable causal gene within the RA locus rs13396472, despite the GWAS variants’ intronic positioning relative to ACOXL, and we identify mechanisms involving SESN3 dysregulation in the RA locus rs4409785. Given these genes’ significant role in T cell development and maturation, our work deepens our comprehension of autoimmune disease pathogenesis and suggesting potential treatment targets.