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This study aimed to develop and validate a multi\u2010omics\u2010based risk prediction model, and to elucidate potential biological mechanisms. Using data from the UK Biobank, Cox proportional hazards and machine learning models (XGBoost and LightGBM) were evaluated for predicting VHD and its subtypes (aortic valve stenosis, AVS; aortic valve regurgitation, AVR; mitral valve regurgitation, MVR). Cox models based on key clinical factors showed the best predictive performance (C\u2010index of 0.75\u20130.81), which was further enhanced by incorporating proteomic data (all C\u2010index &gt; 0.81) but not by genomic or metabolomic data. Notably, a simplified 10\u2010year model comprising only four top proteins maintained favorable performance (C\u2010index of 0.75\u20130.82). Cluster analysis identified blood pressure and lipid levels as leading modifiable risk factors for VHD onset. Functional enrichment analysis revealed that VHD is primarily associated with protease inhibition, AVS with fibrotic and matrix metabolic pathways, and MVR with immune\u2010inflammatory activation. Mendelian randomization and Bayesian colocalization analyses suggested causal associations between CNTN5 and CD8A with risks of AVS and MVR, whilst IGFBP7 showed a reverse\u2010direction association with AVS. These findings highlight promising avenues for early diagnostic biomarkers and potential precision\u2010targeted therapies.<\/jats:p>","DOI":"10.1002\/advs.76345","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T15:58:10Z","timestamp":1783353490000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Harnessing Large\u2010Scale Multi\u2010Omics Data for Risk Prediction and Deep Phenotyping of Valvular Heart Diseases in the General Population"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4588-7942","authenticated-orcid":false,"given":"Zhihao","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Biostatistics School of Public Health Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2678-5689","authenticated-orcid":false,"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics School of Public Health Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics School of Public Health Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics School of Public Health Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0019-0014","authenticated-orcid":false,"given":"Canqing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics School of Public Health Peking University  Beijing China"},{"name":"Peking University Center for Public Health and Epidemic Preparedness &amp; Response  Beijing China"},{"name":"Ministry of Education Key Laboratory of Epidemiology of Major Diseases (Peking University)  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics School of Public Health Peking University  Beijing China"},{"name":"Peking University Center for Public Health and Epidemic Preparedness &amp; Response  Beijing China"},{"name":"Ministry of Education Key Laboratory of Epidemiology of Major Diseases (Peking University)  Beijing China"},{"name":"State Key Laboratory of Vascular Homeostasis and Remodeling Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6275-1147","authenticated-orcid":false,"given":"Eric Yuk Fai","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Family Medicine and Primary Care Li Ka Shing Faculty of Medicine The University of Hong Kong  Hong Kong SAR China"},{"name":"Centre for Safe Medication Practice and Research Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicine The University of Hong Kong  Hong Kong SAR China"},{"name":"The Institute of Cardiovascular Science and Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong  Hong Kong SAR China"},{"name":"Advanced Data Analytics for Medical Science Limited  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8041-7791","authenticated-orcid":false,"given":"Lu","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Epidemiology School of Public Health and Tropical Medicine Tulane University  New Orleans Louisiana USA"},{"name":"Department of Nutrition Harvard T.H. 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