Journal of translational autoimmunity · 2026
Integrative post-GWAS analysis prioritizes immune regulatory pathways and candidate effector signals in systemic lupus erythematosus.
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Modhukur Vijayachitra, Khatun Masuma, Patel Naisarg, S Sajitha Lulu, Lingasamy Prakash, Salumets Andres
Аннотация
BACKGROUND: Systemic lupus erythematosus (SLE) has a complex polygenic architecture, but translating genome-wide association signals into biologically interpretable candidates remains challenging. We applied an integrative post-GWAS framework to refine SLE-associated loci and prioritize candidate regulatory mechanisms.
METHODS: European-ancestry SLE GWAS summary statistics from FinnGen and Bentham et al. were meta-analysed, comprising 8417 cases and 354,277 controls. After quality filtering, 6,782,131 SNPs were retained. Downstream analyses included LAVA regional prioritization, Bayesian colocalization with GTEx v8 whole-blood and spleen eQTLs, independent replication in the Julià et al. Spanish cohort, pathway enrichment, bivariate LAVA cross-trait local genetic correlation, and therapeutic annotation.
RESULTS: The discovery meta-analysis identified 46 genome-wide significant SLE-associated loci, including putative novel signals requiring database/literature qualification. LAVA identified 14 candidate index variants across 12 high-confidence regions, of which nine index variants were retained as the primary prioritized set based on LAVA support and/or convergent regulatory evidence. The strongest association mapped to the chr6p21.3/MHC region (rs389884), where four genes showed colocalization support, including CLIC1 in whole blood and C4A in spleen. Because the chr6p21.3/MHC rs389884 region lead variant was unavailable for replication and no suitable proxy was identified, this signal was interpreted as an emerging candidate for functional validation rather than a replicated causal signal. Seven available variants replicated with concordant effects. An exploratory Roadmap immune chromatin-state overlap analysis placed 15 of 45 non-MHC lead variants (33.3%) directly, and 34 of 45 (75.6%) within ±10 kb, in active immune enhancer/promoter states. Pathway analyses highlighted type I interferon, JAK-STAT signaling, cytokine regulation, and antigen presentation, while bivariate LAVA analyses supported shared local genetic architecture with rheumatoid arthritis, systemic sclerosis, and Sjögren syndrome.
CONCLUSIONS: This integrative post-GWAS analysis refines SLE association signals into biologically interpretable candidate regions and supports interferon and JAK-STAT signaling as central genetically supported pathways in SLE.
METHODS: European-ancestry SLE GWAS summary statistics from FinnGen and Bentham et al. were meta-analysed, comprising 8417 cases and 354,277 controls. After quality filtering, 6,782,131 SNPs were retained. Downstream analyses included LAVA regional prioritization, Bayesian colocalization with GTEx v8 whole-blood and spleen eQTLs, independent replication in the Julià et al. Spanish cohort, pathway enrichment, bivariate LAVA cross-trait local genetic correlation, and therapeutic annotation.
RESULTS: The discovery meta-analysis identified 46 genome-wide significant SLE-associated loci, including putative novel signals requiring database/literature qualification. LAVA identified 14 candidate index variants across 12 high-confidence regions, of which nine index variants were retained as the primary prioritized set based on LAVA support and/or convergent regulatory evidence. The strongest association mapped to the chr6p21.3/MHC region (rs389884), where four genes showed colocalization support, including CLIC1 in whole blood and C4A in spleen. Because the chr6p21.3/MHC rs389884 region lead variant was unavailable for replication and no suitable proxy was identified, this signal was interpreted as an emerging candidate for functional validation rather than a replicated causal signal. Seven available variants replicated with concordant effects. An exploratory Roadmap immune chromatin-state overlap analysis placed 15 of 45 non-MHC lead variants (33.3%) directly, and 34 of 45 (75.6%) within ±10 kb, in active immune enhancer/promoter states. Pathway analyses highlighted type I interferon, JAK-STAT signaling, cytokine regulation, and antigen presentation, while bivariate LAVA analyses supported shared local genetic architecture with rheumatoid arthritis, systemic sclerosis, and Sjögren syndrome.
CONCLUSIONS: This integrative post-GWAS analysis refines SLE association signals into biologically interpretable candidate regions and supports interferon and JAK-STAT signaling as central genetically supported pathways in SLE.