{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T20:45:20Z","timestamp":1793997920234,"version":"4.8.0"},"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM121325"],"award-info":[{"award-number":["P20GM121325"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006545","name":"National Institute on Minority Health and Health Disparities","doi-asserted-by":"publisher","award":["1R21MD013681"],"award-info":[{"award-number":["1R21MD013681"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Previous study has established two polygenic scores (PGSs) related to femoral neck bone mineral density (BMD) (<jats:italic>PGS<\/jats:italic>_<jats:italic>FNBMD<\/jats:italic><jats:sub><jats:italic>ldpred<\/jats:italic><\/jats:sub>) and total body BMD (<jats:italic>PGS<\/jats:italic>_<jats:italic>TBBMD<\/jats:italic><jats:sub><jats:italic>ldpred<\/jats:italic><\/jats:sub>) that are associated with fracture risk. However, these findings have not yet been externally validated in an independent cohort.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Objectives<\/jats:title>\n<jats:p>This study aimed to validate the predictive performance of the two established PGSs and to investigate whether adding PGSs to the Fracture Risk Assessment Tool (FRAX) improves the predictive ability of FRAX in identifying women at high risk of major osteoporotic fracture (MOF) and hip fractures (HF).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Methods<\/jats:title>\n<jats:p>The study used the Women\u2019s Health Initiative (WHI) cohort of 9,000 postmenopausal women of European ancestry. Cox Proportional Hazard Models were used to assess the association between each PGS and MOF\/HF risk. Four models were formulated to investigate the effect of adding PGSs to the FRAX risk factors: (1) Base model: FRAX risk factors; (2) Base model + <jats:italic>PGS<\/jats:italic>_<jats:italic>FNBMD<\/jats:italic><jats:sub><jats:italic>ldpred<\/jats:italic><\/jats:sub>; (3) Base model + <jats:italic>PGS<\/jats:italic>_<jats:italic>TBBMD<\/jats:italic><jats:sub><jats:italic>ldpred<\/jats:italic><\/jats:sub>; (4) Base model + metaPGS. The reclassification ability of models with PGS was further assessed using the Net Reclassification Improvement (NRI) and the Integrated discrimination improvement (IDI).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Results<\/jats:title>\n<jats:p>The study found that the PGSs were not significantly associated with MOF or HF after adjusting for FRAX risk factors. The FRAX base model showed moderate discrimination of MOF and HF, with a C-index of 0.623 (95% CI, 0.609 to 0.641) and 0.702 (95% CI, 0.609 to 0.718), respectively. Adding PGSs to the base FRAX model did not improve the ability to discriminate MOF or HF. Reclassification analysis showed that compared to the model without PGS, the model with <jats:italic>PGS<\/jats:italic>_<jats:italic>TBBMD<\/jats:italic><jats:sub><jats:italic>ldpred<\/jats:italic><\/jats:sub> (1.2%, p = 0.04) and metaPGS (1.7%, p = 0.05) improve the reclassification of HF, but not MOF.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>The findings suggested that incorporating genetic information into the FRAX tool has minimal improvement in predicting HF risk for elderly Caucasian women. These results highlight the need for further research to identify other factors that may contribute to fracture risk in elderly Caucasian women.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0286689","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T17:29:48Z","timestamp":1685640588000},"page":"e0286689","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Validation of a genome-wide polygenic score in improving fracture risk assessment beyond the FRAX tool in the Women\u2019s Health Initiative study"],"prefix":"10.1371","volume":"18","author":[{"given":"Xiangxue","family":"Xiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4679-8903","authenticated-orcid":true,"given":"Qing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,6,1]]},"reference":[{"key":"pone.0286689.ref001","doi-asserted-by":"crossref","first-page":"46","DOI":"10.5152\/eurjrheum.2016.048","article-title":"An overview and management of osteoporosis","volume":"4","author":"T S\u00f6zen","year":"2017","journal-title":"Eur J Rheumatol"},{"key":"pone.0286689.ref002","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1007\/s00198-006-0172-4","article-title":"An estimate of the worldwide prevalence and disability associated with osteoporotic fractures","volume":"17","author":"O Johnell","year":"2006","journal-title":"Osteoporos Int"},{"key":"pone.0286689.ref003","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1210\/er.2009-0044","article-title":"Genetics of osteoporosis","volume":"31","author":"SH Ralston","year":"2010","journal-title":"Endocr Rev"},{"key":"pone.0286689.ref004","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1359\/JBMR.041015","article-title":"Risk of wrist fracture in women is heritable and is influenced by genes that are largely independent of those influencing BMD","volume":"20","author":"T Andrew","year":"2005","journal-title":"J Bone Miner Res"},{"key":"pone.0286689.ref005","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1001\/archinte.165.16.1825","article-title":"Genetic liability to fractures in the elderly","volume":"165","author":"K Micha\u00eblsson","year":"2005","journal-title":"Arch Intern Med"},{"key":"pone.0286689.ref006","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1359\/jbmr.1997.12.12.2076","article-title":"Genetic influences on muscle strength, lean body mass, and bone mineral density: a twin study","volume":"12","author":"NK Arden","year":"1997","journal-title":"J Bone Miner Res"},{"key":"pone.0286689.ref007","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.bone.2019.04.005","article-title":"The genetic architecture of osteoporosis and fracture risk","volume":"126","author":"K Trajanoska","year":"2019","journal-title":"Bone"},{"key":"pone.0286689.ref008","doi-asserted-by":"crossref","first-page":"d3651","DOI":"10.1136\/bmj.d3651","article-title":"Predicting risk of osteoporotic and hip fracture in the United Kingdom: prospective independent and external validation of QFractureScores","volume":"342","author":"GS Collins","year":"2011","journal-title":"BMJ"},{"key":"pone.0286689.ref009","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1007\/s00198-008-0588-0","article-title":"Development of prognostic nomograms for individualizing 5-year and 10-year fracture risks","volume":"19","author":"ND Nguyen","year":"2008","journal-title":"Osteoporos Int"},{"key":"pone.0286689.ref010","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s00198-007-0543-5","article-title":"FRAX and the assessment of fracture probability in men and women from the UK","volume":"19","author":"JA Kanis","year":"2008","journal-title":"Osteoporos Int"},{"key":"pone.0286689.ref011","doi-asserted-by":"crossref","first-page":"e83436","DOI":"10.1371\/journal.pone.0083436","article-title":"FRAX\u00ae: Prediction of Major Osteoporotic Fractures in Women from the General Population","volume":"8","author":"K Briot","year":"2014","journal-title":"The OPUS Study. 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