{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T18:47:40Z","timestamp":1782067660626,"version":"3.54.5"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Current genetic testing for coronary artery disease (CAD) primarily targets monogenic variants in individuals with severe hypercholesterolemia. Whether supplementing monogenic testing with polygenic risk scores for CAD and Lp(a; lipoprotein[a]) levels [PRS\n                      <jats:sub>Lp(a)<\/jats:sub>\n                      ] improves identification of high-risk individuals in the general population remains understudied.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      A genetic probability for CAD (GenProb\n                      <jats:sub>CAD<\/jats:sub>\n                      ), incorporating monogenic pathogenic variants (PVs), polygenic risk scores for CAD, and PRS\n                      <jats:sub>Lp(a)<\/jats:sub>\n                      was developed using Cox regression in 226\u2009145 UK Biobank participants, validated in the remaining 226\u2009145 UK Biobank participants, and applied to 20\u2009477 participants of the Genomic Health Initiative, a community-based health care biobank. Predictive performance was evaluated and adjusted for clinical risk factors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      In the UK Biobank development cohort, PVs, polygenic risk scores for CAD and PRS\n                      <jats:sub>Lp(a)<\/jats:sub>\n                      were each independently associated with CAD. In the UK Biobank validation cohort, GenProb\n                      <jats:sub>CAD<\/jats:sub>\n                      outperformed PVs and the polygenic risk score in predicting CAD and reclassified risk among PV carriers. GenProb\n                      <jats:sub>CAD<\/jats:sub>\n                      identified 16% of participants as high risk, 46-fold more than PV carriers (0.35%), with comparable observed CAD prevalence (15.60% versus 15.43%). Nearly 50% of CAD with high-risk GenProb\n                      <jats:sub>CAD<\/jats:sub>\n                      were premature. GenProb\n                      <jats:sub>CAD<\/jats:sub>\n                      also independently predicted incident CAD after adjusting for clinical risk factors. Importantly, high-risk individuals defined by GenProb\n                      <jats:sub>CAD<\/jats:sub>\n                      showed consistently elevated CAD incidence across all low-density lipoprotein cholesterol strata. When UK Biobank-derived coefficients and cutoffs were applied in the Genomic Health Initiative, GenProb\n                      <jats:sub>CAD<\/jats:sub>\n                      substantially outperformed the PV-only strategy, identifying 1966 high-risk participants (345 developed CAD), far exceeding the 20 PV carriers detected among those with low-density lipoprotein cholesterol \u2265190 mg\/dL (5 developed CAD). A universal genetic testing strategy using GenProb\n                      <jats:sub>CAD<\/jats:sub>\n                      would hypothetically identify 20.75% of all incident CAD, 69-fold higher than current monogenic testing (0.3%). Results were generally consistent across ancestry populations, although the sample size of non-European participants was limited.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      GenProb\n                      <jats:sub>CAD<\/jats:sub>\n                      , a novel integrated genetic risk tool combining monogenic PVs, polygenic risk scores for CAD, and PRS\n                      <jats:sub>Lp(a)<\/jats:sub>\n                      , improves identification of individuals at high genetic risk for CAD across diverse populations.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.125.005494","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T09:00:18Z","timestamp":1775811618000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Development of an Integrated Monogenic and Polygenic Risk Assessment Tool for Coronary Artery Disease and Its Application in a Community-Based Health Care Biobank"],"prefix":"10.1161","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1343-8752","authenticated-orcid":true,"given":"Jianfeng","family":"Xu","sequence":"first","affiliation":[{"name":"Program for Genomic Translational Research, Endeavor Health, Evanston, IL (J.X., Z.S., H.T., J.W., A.A., S.L.Z., B.T.H.)."},{"name":"University of Chicago Pritzker School of Medicine, IL (J.X., B.T.H., A.R.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6321-950X","authenticated-orcid":true,"given":"Zhuqing","family":"Shi","sequence":"additional","affiliation":[{"name":"Program for Genomic Translational Research, Endeavor Health, Evanston, IL (J.X., Z.S., H.T., J.W., A.A., S.L.Z., B.T.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumeet A.","family":"Khetarpal","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center and Division of Cardiology, Department of Medicine, University of Virginia School of Medicine, Charlottesville (S.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley J.","family":"Mulford","sequence":"additional","affiliation":[{"name":"Genomic Health Initiative (A.J.M., A.R.S.), Endeavor Health, Evanston, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osama","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute (O.S., D.J.D., A.Q.), Endeavor Health, Evanston, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huy","family":"Tran","sequence":"additional","affiliation":[{"name":"Program for Genomic Translational Research, Endeavor Health, Evanston, IL (J.X., Z.S., H.T., J.W., A.A., S.L.Z., B.T.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9778-1239","authenticated-orcid":true,"given":"Jun","family":"Wei","sequence":"additional","affiliation":[{"name":"Program for Genomic Translational Research, Endeavor Health, Evanston, IL (J.X., Z.S., H.T., J.W., A.A., S.L.Z., B.T.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6941-0773","authenticated-orcid":true,"given":"Annabelle","family":"Ashworth","sequence":"additional","affiliation":[{"name":"Program for Genomic Translational Research, Endeavor Health, Evanston, IL (J.X., Z.S., H.T., J.W., A.A., S.L.Z., B.T.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6088-9716","authenticated-orcid":true,"given":"S. Lilly","family":"Zheng","sequence":"additional","affiliation":[{"name":"Program for Genomic Translational Research, Endeavor Health, Evanston, IL (J.X., Z.S., H.T., J.W., A.A., S.L.Z., B.T.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4696-3940","authenticated-orcid":true,"given":"David","family":"Duggan","sequence":"additional","affiliation":[{"name":"Translational Genomics Research Institute, Part of City of Hope, Phoenix, AZ (D.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian T.","family":"Helfand","sequence":"additional","affiliation":[{"name":"Program for Genomic Translational Research, Endeavor Health, Evanston, IL (J.X., Z.S., H.T., J.W., A.A., S.L.Z., B.T.H.)."},{"name":"University of Chicago Pritzker School of Medicine, IL (J.X., B.T.H., A.R.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry M.","family":"Dunnenberger","sequence":"additional","affiliation":[{"name":"Neaman Center for Personalized Medicine (H.M.D., P.J.H.), Endeavor Health, Evanston, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8397-4078","authenticated-orcid":true,"given":"Peter J.","family":"Hulick","sequence":"additional","affiliation":[{"name":"Neaman Center for Personalized Medicine (H.M.D., P.J.H.), Endeavor Health, Evanston, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1470-8280","authenticated-orcid":true,"given":"David J.","family":"Davidson","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute (O.S., D.J.D., A.Q.), Endeavor Health, Evanston, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit V.","family":"Khera","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA (A.V.K.)."},{"name":"Department of Medicine, Harvard Medical School, Boston, MA (A.V.K., A.P.P.)."},{"name":"Verve Therapeutics, Boston, MA (A.V.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7871-9638","authenticated-orcid":true,"given":"Aniruddh P.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Medicine, Harvard Medical School, Boston, MA (A.V.K., A.P.P.)."},{"name":"Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (A.P.P.)."},{"name":"Mass General Brigham Heart and Vascular Institute, Boston, MA (A.P.P.)."},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston (A.P.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R.","family":"Sanders","sequence":"additional","affiliation":[{"name":"University of Chicago Pritzker School of Medicine, IL (J.X., B.T.H., 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