Multi-layered functional genomics prioritizes candidate effectors and regulatory mechanisms of ankylosing spondylitis
Abstract
Background: Ankylosing spondylitis (AS) is a chronic inflammatory arthropathy with heritability estimated at approximately 90%, yet the effector genes and regulatory mechanisms beyond the well-established HLA-B*27 association remain incompletely defined. Translating GWAS-identified loci into biological insight requires integration of calibrated association statistics, gene-level prioritization, fine-mapping, molecular prediction, and experimental follow-up.
Methods: We performed a GWAS meta-analysis of 7,551 AS cases and 1,258,581 controls from the Million Veteran Program, FinnGen, and UK Biobank whole-genome sequencing cohorts. The post-GWAS analysis combined causal transcriptome-wide association study (cTWAS) across four immune-relevant tissues, colocalization, four-method fine-mapping, Geneformer V2 in-silico perturbation, AlphaGenome variant-effect prediction, cross-trait LD-score regression (LDSC), pathway enrichment, structured druggability assessment, and siRNA knockdown in Jurkat T cells. We added LDSC calibration, per-cohort Q-Q plots, heterogeneity summaries, and leave-one-cohort-out sensitivity analyzes for revised quality control.
Results: The meta-analysis identified 30 genome-wide significant loci harboring 26,178 significant variants. After LDSC-compatible quality control, the meta-analysis showed lambda_GC = 1.09, LDSC intercept = 1.045 (SE = 0.009), and attenuation ratio = 0.365 (SE = 0.075); per-cohort lambda_GC values were 1.027, 1.080, and 1.018 for MVP,…
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