Clark AD, Nair N, Anderson AE, et al. - Given that elucidating regulatory mechanisms by which noncoding risk variants impact the cell-mediated pathogenesis of immune-mediated disease (IMD) has surfaced as a priority in the post–genome-wide association study era, and therefore, researchers utilized whole-genome methylation and transcriptional data, to explore novel insight into genetic mechanisms of adaptive immune dysregulation to aid prioritize molecular pathways for targeting in rheumatoid arthritis (RA) and associated immune pathologies. They collected data from more than 100 genotyped and phenotyped patients having inflammatory arthritis, all of whom were naive to immunomodulatory therapies. Strong evidence demonstrating the regulation of cis-CpG methylation in CD4⁺ T and/or B cells by disease-associated DNA variants, at 37% RA loci, was generated. Employing paired, cell-specific transcriptomic data as well as causal inference examination, they recognized instances where gene expression is mediated by site-specific DNA methylation, including FCRL3 in both cell types and ORMDL3/GSDMB, IL6ST/ANKRD55, and JAZF1 in CD4⁺ T cells. Mechanisms common to RA as well as other IMDs including multiple sclerosis and asthma were revealed by a number of genes regulated in this way, and this allowed the discrimination of these from osteoarthritis. Ultimately, they confirmed the perceived effects experimentally. In this work, essential mechanisms of genetic risk in RA as well as the broader context of immune dysregulation was highlighted. DNA methylation profiling was corroborated as a tool with utility for causal gene prioritization and, potentially, for therapeutic targeting in complex IMD.