Background Genetic factors play key roles in the pathogenesis of systemic lupus erythematosus (SLE). In the last one and half decade, genome-wide association studies (GWAS) have seen enormous successes, revealing nearly 200 associated loci. However, for large number of loci, the causal variant(s), the association mechanism(s) are unclear. For some, the target gene(s) are unknown or controversial. Lack of functional understanding is the major challenge for translating genetic findings into clinical applications.
Methods In this study, we compared the association signals for SLE with the associations from 14 other autoimmune diseases, using linkage disequilibrium and conditional analyses to identify the shared and specific association signals. We annotated these signals using genomic resources such as eQTL, histone marks, chromatin accessibility, TF binding, and promoter interaction. Relevant cell types and signaling networks are constructed and compared among these diseases.
Results Analyzing the association signals between SLE and other autoimmune diseases and genomic annotations allow us to have a better grip on the causal genes and association mechanisms. Specific associations are identified for SLE even when the locus is shared with other diseases, including in IKZF1, ETS1, IL12A, DUSP22, IL12RB2, and CD40. Specific target genes, distinct cell types and signaling networks are detected for SLE. The differences suggested by these analyses raise intriguing questions on the shared and unique mechanisms of these autoimmune diseases.
Conclusions Genetic analysis and genomic annotations of associated loci for SLE in comparison with associations with 14 other autoimmune diseases facilitate the identification of the causal genes and the association mechanisms for SLE. The signals that are shared, or SLE-specific, or lack thereof shed new light on this prototype autoimmune disease from different angles.
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