Genetic variants differentially associated with rheumatoid arthritis and systemic lupus erythematosus reveal the disease-specific biology

Two rheumatic autoimmune diseases, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), have distinct clinical features despite their genetic similarities. We hypothesized that disease-specific variants exclusively associated with only one disease could contribute to disease-specific phenotypes. We calculated the strength of disease specificity for each variant in each disease against the other disease using summary association statistics reported in the largest genome-wide association studies of RA and SLE. Most of highly disease-specific associations were explained by non-coding variants that were significantly enriched within regulatory regions (enhancers or H3K4me3 histone modification marks) in specific cell or organ types. (e.g., In RA, regulatory T primary cells, CD4+ memory T primary cells, thymus and lung; In SLE, CD19+ B primary cells, mobilized CD34+ primary cells, regulatory T primary cells and monocytes). Consistently, genes in the disease-specific loci were significantly involved in T cell- and B cell-related gene sets in RA and SLE. In summary, this study identified disease-specific variants between RA and SLE, and provided statistical evidence for disease-specific cell types, organ and gene sets that may drive the disease-specific phenotypes.