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The purpose of this study was to develop and validate a polygenic score (PGS) for CRF (CRF\n                    <jats:sub>PGS<\/jats:sub>\n                    ) and assess its associations with cardiovascular disease (CVD) and all-cause mortality. We hypothesized that the CRF\n                    <jats:sub>PGS<\/jats:sub>\n                    would demonstrate similar cardioprotective benefits as the CRF phenotype. Effect estimates from a genome-wide association study on directly measured CRF in the Tr\u00f8ndelag Health Study (HUNT;\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20094525) were used in a Bayesian regression framework to develop multiple PGSs in an independent cohort from the UK Biobank (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200965,165). The top performing score was applied in the HUNT target cohort, excluding the discovery sample (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200982,109). The PGS-CRF association varied considerably as a function of model fit and phenotypic accuracy. There was a difference of 1.55 [95% confidence interval: 1.26, 1.84]\u00a0 mL\u00b7kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00b7min\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00a0between the bottom and top decile of the CRF\n                    <jats:sub>PGS<\/jats:sub>\n                    . Moreover, a high CRF\n                    <jats:sub>PGS<\/jats:sub>\n                    demonstrated cardioprotective effects, with reduced risk for CVD, myocardial infarction, hypertension, and all-cause mortality. Additionally, in women, we observed that the CRF\n                    <jats:sub>PGS<\/jats:sub>\n                    predisposed to lower risk of heart failure and hypertrophic cardiomyopathy. We developed the first PGS for CRF using gold standard phenotypes and multiple independent cohorts. Genetic susceptibility to high CRF may have a clinically meaningful impact on the phenotype. The CRF\n                    <jats:sub>PGS<\/jats:sub>\n                    was better to identify individuals with slightly higher lifelong levels of CRF, which appears to protect against cardiovascular morbidity and mortality.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-28894-7","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T16:15:04Z","timestamp":1765901704000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Polygenic prediction of cardiorespiratory fitness in the Tr\u00f8ndelag health study (HUNT)"],"prefix":"10.1038","volume":"16","author":[{"given":"Karsten","family":"\u00d8vretveit","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Klevjer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben M.","family":"Brumpton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrik","family":"Wisl\u00f8ff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Hveem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Bye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,16]]},"reference":[{"key":"28894_CR1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2018.3605","volume":"1","author":"K Mandsager","year":"2018","unstructured":"Mandsager, K. et al. 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