Abstract
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.
Highlights
Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are well-characterized rheumatic autoimmune diseases with >60% heritability[1,2]
A total of 8,031,027 autosomal single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 0.5% and imputation quality score ≥0.5 in both rheumatoid arthritis (RA) and SLE datasets were analyzed in this study
To avoid inflated estimates of the association similarity or dissimilarity in two diseases due to multiple SNPs in linkage disequilibrium (LD), we extracted 369,955 SNPs that were not correlated with each other (r2 < 0.2) within a 2-Mb flanking window based on the genotypes in the European populations of the 1000 Genomes Projects
Summary
Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are well-characterized rheumatic autoimmune diseases with >60% heritability[1,2]. Some variants in immune-related genes such as HLA-DRB1, PTPN22, STAT4, and TNFAIP3 were reported to contribute to risk of RA and SLE8–11. These pleiotropic variants associated with both RA and SLE strongly suggest that the pathogenesis leading to immune dysfunction is partially shared between these two autoantibody-producing diseases. Evidence of pleiotropic variants in similar diseases motivated cross-disease meta-analyses[12,13] and phenome-wide association studies to identify pleiotropic variants that explain common pathogenesis in different diseases. We comprehensively investigated the dissimilarity in disease-variant associations between RA and SLE at the genome-wide level, and identified highly disease-specific variants that map to disease-specific cell types and pathways
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