{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T05:01:28Z","timestamp":1780290088125,"version":"3.54.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"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                      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\n                      <jats:italic>HLA-B*27<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\u00a0=\u00a00.009), and attenuation ratio = 0.365 (SE\u00a0=\u00a00.075); per-cohort lambda_GC values were 1.027, 1.080, and 1.018 for MVP, FinnGen, and UKB-WGS, respectively. cTWAS prioritized 64 causal-candidate genes (posterior inclusion probability [PIP] &amp;gt; 0.5), with gene expression explaining 19.5% of AS heritability. Seven genes showed convergent cTWAS and colocalization evidence (\n                      <jats:italic>TBKBP1<\/jats:italic>\n                      ,\n                      <jats:italic>TIMD4<\/jats:italic>\n                      ,\n                      <jats:italic>HABP4<\/jats:italic>\n                      ,\n                      <jats:italic>XCL1<\/jats:italic>\n                      ,\n                      <jats:italic>USP22<\/jats:italic>\n                      ,\n                      <jats:italic>ABO<\/jats:italic>\n                      ,\n                      <jats:italic>ACTA2<\/jats:italic>\n                      ). Four-method fine-mapping identified 64 consensus variants, while heterogeneity and leave-one-cohort-out analyzes highlighted cohort-sensitive signals, particularly in the MHC and other high-I2 regions. Cross-trait LDSC showed positive genetic correlations with inflammatory bowel disease and psoriasis, but not rheumatoid arthritis or the available uveitis proxy. siRNA knockdown provided functional support for\n                      <jats:italic>TBKBP1<\/jats:italic>\n                      and\n                      <jats:italic>XCL1<\/jats:italic>\n                      in Jurkat T cells, while\n                      <jats:italic>TIMD4<\/jats:italic>\n                      behaved as a context-specific myeloid\/T-cell contrast.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This convergent evidence framework prioritizes AS candidate genes and regulatory variants while separating statistical prioritization from experimental support. The revised analyzes strengthen calibration, heterogeneity reporting, cross-disease context, and translational interpretation, nominating immune and regulatory hypotheses for follow-up rather than definitive therapeutic targets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1859310","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T04:19:24Z","timestamp":1780287564000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-layered functional genomics prioritizes candidate effectors and regulatory mechanisms of ankylosing spondylitis"],"prefix":"10.3389","volume":"17","author":[{"given":"Fanyu","family":"Meng","sequence":"first","affiliation":[{"name":"The Sixth School of Clinical Medicine, Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]},{"name":"Xinjiang Institute of Spinal Surgery, The Sixth Affiliated Hospital of Xinjiang Medical 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Clinical Medicine, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruifeng","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiani","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Yuan","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Guilin Medical University","place":["Guilin, 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