Integrative post-GWAS analysis prioritizes interferon-linked regulatory and splicing-associated variants at the TNFSF10 locus in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by interferon-driven immune dysregulation. Although TNFSF10/TRAIL has been implicated in immune regulation, genetic and transcript-level features linking interferon-related susceptibility loci to TNFSF10 remain unclear. Here, we performed an integrative post-GWAS analysis using SLE GWAS summary statistics from the Taiwan Precision Medicine Initiative, combined with pathway enrichment, motif annotation, population-specific linkage disequilibrium, GTEx eQTL/sQTL profiling, public SLE RNA-seq, GWAS-QTL colocalization, and chromatin regulatory datasets. Interferon-related genes IRF5, IRF8, and STAT4 showed putative regulatory links to TNFSF10 and population-dependent allele-frequency and linkage-disequilibrium patterns. Public SLE RNA-seq supported increased TNFSF10 expression in SLE. Downstream TNFSF10 variants, particularly near terminal intronic and 3'UTR regions, were associated predominantly with splicing QTL signals in immune-relevant tissues and overlapped with candidate regulatory annotations. Together, these findings support an integrative genomic framework for prioritizing candidate regulatory and splicing-associated features at the TNFSF10 locus in SLE.