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However, existing genetic risk scores (GRS) only provide a few percent predictive power for osteoporotic fracture.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We derived and validated a novel genome-wide polygenic score (GPS) comprised of 103,155 common genetic variants to quantify this susceptibility and tested this GPS prediction ability in an independent dataset (n\u2009=\u200915,776).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among postmenopausal women, we found a fivefold gradient in the risk of major osteoporotic fracture (MOF) (p\u2009&lt;\u20090.001) and a 15.25-fold increased risk of severe osteoporosis (p\u2009&lt;\u20090.001) across the GPS deciles. Compared with the remainder of the GPS distribution, the top GPS decile was associated with a 3.59-, 2.48-, 1.92-, and 1.58-fold increased risk of any fracture, MOF, hip fracture, and spine fracture, respectively. The top GPS decile also identified nearly twofold more high-risk osteoporotic patients than the top decile of conventional GRS based on 1103 conditionally independent genome-wide significant SNPs. Although the relative risk of severe osteoporosis for postmenopausal women at around 50 is relatively similar, the cumulative incident at 20-year follow-up is significantly different between the top GPS decile (13.7%) and the bottom decile (&lt;\u20091%). In the subgroup analysis, the GPS transferability in non-Hispanic White is better than in other racial\/ethnic groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This new method to quantify inherited susceptibility to osteoporosis and osteoporotic fracture affords new opportunities for clinical prevention and risk assessment.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12967-023-03974-2","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T06:29:07Z","timestamp":1676528947000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Genome-wide polygenic risk score for major osteoporotic fractures in postmenopausal women using associated single nucleotide polymorphisms"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4679-8903","authenticated-orcid":false,"given":"Qing","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9258-5397","authenticated-orcid":false,"given":"Jongyun","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"3974_CR1","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1007\/BF01880454","volume":"1","author":"World Health Organization","year":"1991","unstructured":"World Health Organization. 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