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This study aims to uncover novel genetic insights into ASCVD through multivariate genomic analysis and molecular structure predictions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analysed genomic data from over 3.8 million individuals across various ASCVD phenotypes, including coronary heart disease, stroke, transient ischemic attack, peripheral artery disease and abdominal aortic aneurysm. Advanced tools such as Genomic Structural Equation Modeling, fine\u2010mapping, FUSION, FOCUS and other functional annotation methods were applied to identify causal single nucleotide polymorphisms associated with ASCVD. Protein structural analysis was performed using AlphaFold3, and AI\u2010driven thermodynamic analysis (ThermoMPNN) assessed the stability and functional consequences of mutations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our analysis revealed 347 genome\u2010wide significant variants linked to ASCVD, distributed across 213 loci. Ninety of these variants were not identified in any of the five input GWAS datasets. Upon cross\u2011referencing with large\u2011scale external GWAS, 19 of the 90 variants showed no prior association with any cardiovascular or metabolic trait, 15 were previously reported only in risk factor GWAS, and 56 had been reported in direct ASCVD endpoint GWAS. The latter group includes the\n                      <jats:italic>DCLRE1B<\/jats:italic>\n                      rs11552449 missense mutation. Nevertheless, AI\u2011based structural and thermodynamic analyses revealed that this mutation (H61Y) disrupts DCLRE1B protein stability, increases conformational flexibility, and alters solvent\u2011accessible surface area\u2014mechanistic insights that have not been previously described.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides a hypothesis\u2011generating genetic landscape of ASCVD, unveiling novel variants and their molecular impacts. These findings enhance our understanding of ASCVD mechanisms and may offer potential avenues pending experimental validation and targeted therapies in cardiovascular disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70732","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T07:09:24Z","timestamp":1783667364000},"source":"Crossref","is-referenced-by-count":1,"title":["Precision medicine for atherosclerotic cardiovascular disease: Integrative genomics maps risk loci and AI\u2010predicted functional consequences"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7851-6379","authenticated-orcid":false,"given":"Liwan","family":"Fu","sequence":"first","affiliation":[{"name":"Center for Non\u2010Communicable Disease Management Department of Neurology Beijing Children's Hospital, Capital Medical University, National Center for Children's Health  Beijing 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