{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T05:38:14Z","timestamp":1792647494578,"version":"4.5.0"},"reference-count":61,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"20","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,10,20]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of mortality worldwide and comprises multiple clinical phenotypes, but their shared genetic architecture remains incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">We integrated genome\u2010wide association study summary statistics for coronary artery disease, peripheral artery disease, large\u2010artery atherosclerotic stroke, and carotid plaque using genomic structural equation modeling to derive a multivariable ASCVD common factor. We applied fine\u2010mapping, multi\u2010marker analysis of genomic annotation, transcriptome\u2010wide association studies, Mendelian randomization, colocalization, mediation analysis, and virtual screening.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      We identified 289 linkage disequilibrium\u2013independent lead single\u2010nucleotide polymorphisms mapping to 177 genomic risk loci; 13 lacked corresponding genome\u2010wide significant signals in the input genome\u2010wide association studies. Eleven had prior genome\u2010wide association study catalog association records, whereas no relevant records were identified for the loci represented by rs2294777 near\n                      <jats:italic toggle=\"no\">SASH1<\/jats:italic>\n                      and rs4843053 near\n                      <jats:italic toggle=\"no\">AKAP13<\/jats:italic>\n                      . Fine\u2010mapping prioritized 26 putative causal variants. Integrated functional summary\u2010based imputation, multi\u2010tissue transcriptome\u2010wide association study, and multi\u2010marker analysis of genomic annotation analyses implicated 123 genes. Enrichment analyses highlighted endothelial cells and H3K27ac\u2010marked regulatory regions. Lipidomic analyses linked higher triacylglycerols and sterol esters to increased multivariable ASCVD common factor risk. Protein Mendelian randomization analyses in deCODE and Fenland prioritized aldehyde dehydrogenase 2 (ALDH2), phosphodiesterase 5A (PDE5A), HtrAserinepeptidase 1 (HTRA1), and transcription elongation factor A2 (TCEA2)\u00a0as candidate targets. Colocalization supported a shared causal variant between TCEA2 and multivariable ASCVD common factor. Mediation analyses suggested partial mediation by diastolic blood pressure for ALDH2, PDE5A, and TCEA2 and by triglycerides for TCEA2. Virtual screening identified candidate compounds with favorable predicted binding to PDE5A and ALDH2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Integrating multivariate genome\u2010wide association study with multi\u2010omics and causal inference analyses identified shared genetic signals associated with ASCVD susceptibility and prioritized candidate protein targets, informing future functional studies and target validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.126.050689","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T11:25:21Z","timestamp":1792149921000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Multivariate Genomic Analysis Reveals Shared Genetic Architecture and Potential Therapeutic Targets for Atherosclerotic Cardiovascular Disease"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2216-6058","authenticated-orcid":false,"given":"Yifeng","family":"Xu","sequence":"first","affiliation":[{"name":"China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5759-1575","authenticated-orcid":false,"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9950-8282","authenticated-orcid":false,"given":"Ruoqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2397-9429","authenticated-orcid":false,"given":"Chengzhi","family":"Hou","sequence":"additional","affiliation":[{"name":"China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1888-6072","authenticated-orcid":false,"given":"Xuan","family":"Sun","sequence":"additional","affiliation":[{"name":"China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7844-0478","authenticated-orcid":false,"given":"Qiyang","family":"Li","sequence":"additional","affiliation":[{"name":"Hubei University of Chinese Medicine","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0977-5468","authenticated-orcid":false,"given":"Chao","family":"Liu","sequence":"additional","affiliation":[{"name":"China Academy of Chinese Medical Sciences","place":["Beijing, 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