{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T05:14:20Z","timestamp":1783314860033,"version":"3.54.6"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>TCTN2<\/jats:italic>\n                      -centered effector-gene hypothesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The prioritization model, used solely as a ranking layer, assigned a high prioritization score (\u2265 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,\n                      <jats:italic>TCTN2<\/jats:italic>\n                      showed the strongest cross-layer convergence, with SMR support in five of six tissues, fibroblast eMAGMA support (P\u00a0=\u00a08.34 \u00d7 10\n                      <jats:sup>-10<\/jats:sup>\n                      ), hypertrophic-chondrocyte enrichment (z = 2.20), and localization to regulatory and inflammatory chondrocyte states. Independent validation showed modestly higher\n                      <jats:italic>TCTN2<\/jats:italic>\n                      abundance in OA than in normal cartilage (delta = 0.45, P\u00a0=\u00a02.8 \u00d7 10\n                      <jats:sup>-2<\/jats:sup>\n                      ), no high-grade-versus-low-grade cartilage shift (logFC = 0.053, FDR\u00a0=\u00a01.0), and strong OA-cartilage eQTL support in both low-grade and high-grade cartilage (q = 4.86 \u00d7 10\u2013\n                      <jats:sup>4<\/jats:sup>\n                      and 1.13 \u00d7 10\n                      <jats:sup>-2<\/jats:sup>\n                      ). In ATDC5 cells,\n                      <jats:italic>Tctn2<\/jats:italic>\n                      knockdown reduced expression to 0.21-fold of Mock and increased\n                      <jats:italic>Col10a1<\/jats:italic>\n                      ,\n                      <jats:italic>Mmp13<\/jats:italic>\n                      , and\n                      <jats:italic>Runx2<\/jats:italic>\n                      to 2.71-, 2.98-, and 3.53-fold, respectively, whereas overexpression and rescue reversed the same markers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This staged analysis nominates\n                      <jats:italic>TCTN2<\/jats:italic>\n                      as a plausible candidate within an unresolved chr12 osteoarthritis locus; ATDC5 perturbation indicates that\n                      <jats:italic>TCTN2<\/jats:italic>\n                      can modulate hypertrophic markers. Because the human-tissue association is directionally discordant, we present a locus-to-cell-state hypothesis rather than a complete genetics-to-mechanism chain, with cross-sectional shifts remaining modest and context-dependent.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1883412","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T04:20:41Z","timestamp":1783311641000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated post-GWAS, single-cell, and functional analyses prioritize TCTN2 at an osteoarthritis locus associated with innate immunity-related cartilage remodeling"],"prefix":"10.3389","volume":"17","author":[{"given":"Changchun","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People\u2019s Hospital South Campus","place":["Shanghai, 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