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

In this study, we present the most extensive dataset of chromatin conformation data with matching gene expression and chromatin accessibility from primary T cells to date. We use this data to enhance our understanding of the different mechanisms by which GWAS variants impact gene regulation and revealing how natural genetic variation alter chromatin accessibility and structure in primary cells at an unprecedented scale. Capitalizing on this vast dataset, 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 is vital for deepening our comprehension of autoimmune disease pathogenesis and suggesting potential treatment targets. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the Wellcome Trust (award references 207491/Z/17/Z and 215207/Z/19/Z), Versus Arthritis (award reference 21754), NIHR Manchester Biomedical Research Centre and the Medical Research Council (award reference MR/N00017X/1). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of The University of Manchester gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes