Lymphocyte DNA methylation mediates genetic risk at shared immune-mediated disease loci

Defining regulatory mechanisms through which noncoding risk variants influence the cell-mediated pathogenesis of immune-mediated disease (IMD) has emerged as a priority in the post-genome-wide association study era.

With a focus on rheumatoid arthritis, we sought new insight into genetic mechanisms of adaptive immune dysregulation to help prioritize molecular pathways for targeting in this and related immune pathologies.

Whole-genome methylation and transcriptional data from isolated CD4⁺ T cells and B cells of more than 100 genotyped and phenotyped patients with inflammatory arthritis, all of whom were naive to immunomodulatory treatments, were obtained. Analysis integrated these comprehensive data with genome-wide association study findings across IMDs and other publicly available resources.

We provide strong evidence that disease-associated DNA variants regulate cis-CpG methylation in CD4⁺ T and/or B cells at 37% RA loci. Using paired, cell-specific transcriptomic data and causal inference testing, we identify examples where site-specific DNA methylation in turn mediates gene expression, including FCRL3 in both cell types and ORMDL3/GSDMB, IL6ST/ANKRD55, and JAZF1 in CD4⁺ T cells. A number of genes regulated in this way highlight mechanisms common to RA and other IMDs including multiple sclerosis and asthma, in turn distinguishing them from osteoarthritis, a primarily degenerative disease. Finally, we corroborate the observed effects experimentally.

Our observations highlight important mechanisms of genetic risk in RA and the wider context of immune dysregulation. They confirm the utility of DNA methylation profiling as a tool for causal gene prioritization and, potentially, therapeutic targeting in complex IMD.