Dynamic regulatory elements in single-cell multimodal data capture autoimmune disease heritability and implicate key immune cell states

In autoimmune diseases such as rheumatoid arthritis (RA), the immune system attacks host tissues[1][1]-[3][2]. Developing a precise understanding of the fine-grained cell states that mediate the genetics of autoimmunity is critical to uncover causal disease mechanisms and develop potentially curative therapies. We leveraged multimodal single-nucleus (sn) RNA-seq and ATAC-seq data across 28,674 cells from the inflamed synovium of 12 donors with arthritis to identify accessible regions of chromatin associated with gene expression patterns that reflect cell states. For 12 autoimmune diseases, we discovered that cell-state-dependent (“dynamic”) peaks in immune cell types disproportionately captured heritability, compared to cell-state-invariant (“cs-invariant”) peaks. These dynamic peaks marked regulatory elements associated with T peripheral helper, regulatory T, dendritic, and STAT1+CXCL10+ myeloid cell states. We argue that dynamic regulatory elements can help identify precise cell states enriched for disease-critical genetic variation. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work is supported in part by funding from the National Institutes of Health (R01AR063759, U01HG012009, UC2AR081023, P01AI148102, U19AI095219, R01AR063709, T32AR007530, T32AR007530) and the Broad Institute. ### 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: Study used samples collected under IRB-approved protocols at Brigham and Women's Hospital and Hospital for Special Surgery. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 This manuscript uses multimodal single-nucleus data that will be released upon publication of the following manuscript: Weinand et al. (in preparation). [1]: #ref-1 [2]: #ref-3