A multilayered post-GWAS analysis pipeline defines functional variants and target genes for systemic lupus erythematosus (SLE).

Objectives: Systemic lupus erythematosus (SLE), an autoimmune disease with incompletely understood etiology, has a strong genetic component. Although genome-wide association studies (GWAS) have revealed multiple SLE susceptibility loci and associated single nucleotide polymorphisms (SNPs), the precise causal variants, target genes, cell types, tissues, and mechanisms of action remain largely unknown. Methods: Here, we report a comprehensive post-GWAS analysis using extensive bioinformatics, molecular modeling, and integrative functional genomic and epigenomic analyses to optimize fine-mapping. We compile and cross-reference immune cell-specific expression quantitative trait loci ( Results: Anchoring on 452 index SNPs, we selected 9,931 high-linkage disequilibrium (r Conclusion: We demonstrate and validate post-GWAS strategies for utilizing multi-dimensional data to prioritize likely causal variants with cognate gene targets underlying SLE pathogenesis. Our results provide a catalog of significantly SLE-associated SNPs and loci, target genes, and likely biochemical mechanisms, to guide experimental characterization.