Integrated post-GWAS, single-cell, and functional analyses prioritize

Background: Post-genome-wide association study (GWAS) interpretation of osteoarthritis (OA) increasingly requires integration with single-cell biology because many risk loci likely act through sterile inflammatory remodeling, regulatory and inflammatory chondrocyte states, and tissue-stress biology rather than through large disease-stage expression shifts. We therefore asked whether a published Transformer-based post-GWAS prioritization strategy could refine a multi-gene chr12 susceptibility locus into a tractable Methods: Using combined hip and knee osteoarthritis summary statistics (213,839 cases and 1,080,481 controls), we built a transfer-learning variant-prioritization layer that scored 20,651,210 variants with 21 engineered features, combined these with LDSC, positional MAGMA, fibroblast and muscle eMAGMA, six-tissue SMR, and fine-mapping, and then integrated the prioritized locus with a 56,000-cell chondrocyte atlas, independent OA cartilage expression resources, OA primary-tissue eQTL maps, and ATDC5 perturbation experiments. Results: The prioritization model, used solely as a ranking layer, assigned a high prioritization score (≥ 0.99) to 17,150 variants, including the chr12 lead rs11611450 (prioritization score 0.999853), and highlighted 6,275 additional non-genome-wide-significant high-priority variants. Positional MAGMA nominated eight Bonferroni-significant genes, and eMAGMA nominated four genes in skeletal muscle and seven in fibroblasts. Within the rs11611450-linked five-gene cluster, Conclusions: This staged analysis nominates