{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T07:37:26Z","timestamp":1765957046933,"version":"3.48.0"},"reference-count":28,"publisher":"World Scientific Pub Co Pte Ltd","issue":"06","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Bioinform. Comput. Biol."],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:p>Graves\u2019 disease (GD) is a common autoimmune disorder. However, the circulating proteins that causally drive its pathogenesis remain largely unconfirmed by genetic evidence. Identifying such proteins is critical for developing novel therapeutics. Methods: We performed a two-sample Mendelian randomization (MR) analysis using genetic instruments for 4907 plasma proteins and summary statistics from a GD genome-wide association study (GWAS) of European ancestry to identify causal proteins. We subsequently conducted protein\u2013protein interaction (PPI) network analysis and used AlphaFold3 to model the structural impact of a key variant, rs41271951, in the top candidate protein, cathepsin S (CTSS). Results: MR analysis identified 23 plasma proteins with putative causal effects on GD risk. Among these, CD5L showed the strongest evidence for colocalization (posterior [Formula: see text]), suggesting a shared causal variant. Network analysis revealed that these proteins converge on a novel complement\u2013ECM\u2013coagulation axis in GD pathogenesis. CTSS emerged as a central hub in this network. AlphaFold3 modeling suggested that the CTSS variant rs41271951 (p.Val7Ala), located within the signal peptide, induces subtle structural perturbations. The primary and most plausible consequence is a reduction in CTSS secretion and circulating levels, as supported by the pQTL data. Conclusion: This multi-omics analysis proposes a novel complement\u2013ECM\u2013coagulation axis in GD. By structurally and functionally linking reduced CTSS abundance and secretion to genetic variation, we identify CTSS as a potential candidate for therapeutic repurposing in GD.<\/jats:p>","DOI":"10.1142\/s0219720025500234","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T10:20:24Z","timestamp":1764325224000},"source":"Crossref","is-referenced-by-count":0,"title":["Mendelian randomization and AlphaFold3 analysis suggest putative causal plasma proteins in graves\u2019 disease"],"prefix":"10.1142","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2546-9390","authenticated-orcid":false,"given":"Bin","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Nanping First Affiliated Hospital of Fujian Medical University, Nanping, P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhanlin","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Nanping First Affiliated Hospital of Fujian Medical University, Nanping, P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liangzhi","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Nanping First Affiliated Hospital of Fujian Medical University, Nanping, P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Nanping First Affiliated Hospital of Fujian Medical University, Nanping, P. R. 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