{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:19:37Z","timestamp":1768569577128,"version":"3.49.0"},"posted":{"date-parts":[[2025,7,7]]},"group-title":"Genetic and Genomic Medicine","reference-count":36,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Cardiorespiratory fitness (CRF) has a strong genetic component and low CRF is a major risk factor for cardiovascular morbidity and mortality. 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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    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                    = 4 525) 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                    = 65 165). The top performing score was applied in the HUNT target cohort, excluding the discovery sample (\n                    <jats:italic>n<\/jats:italic>\n                    = 82 109).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The PGS-CRF association varied considerably as a function of model fit and phenotypic accuracy. In the target population, we observed a difference in CRF of 1.55 [95% confidence interval: 1.26, 1.84] mL\u00b7kg\n                    <jats:sup>-1<\/jats:sup>\n                    \u00b7min\n                    <jats:sup>-1<\/jats:sup>\n                    between 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. We also found that the CRF\n                    <jats:sub>PGS<\/jats:sub>\n                    predisposed to lower risk of heart failure and hypertrophic cardiomyopathy in women.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>A PGS for CRF derived from gold-standard phenotypes captures small, but potentially clinical meaningful variations in CRF, and is associated with reduced risk of cardiovascular morbidity and mortality. Heterogeneity in CRF phenotyping in large populations remains a challenge to PGS development and refinement.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.07.25330991","type":"posted-content","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T17:43:20Z","timestamp":1751910200000},"source":"Crossref","is-referenced-by-count":0,"title":["Polygenic prediction of cardiorespiratory fitness: The HUNT Study"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5528-0674","authenticated-orcid":false,"given":"Karsten","family":"\u00d8vretveit","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8372-276X","authenticated-orcid":false,"given":"Marie","family":"Klevjer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3058-1059","authenticated-orcid":false,"given":"Ben M.","family":"Brumpton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7211-3587","authenticated-orcid":false,"given":"Ulrik","family":"Wisl\u00f8ff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8157-9744","authenticated-orcid":false,"given":"Kristian","family":"Hveem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1259-5542","authenticated-orcid":false,"given":"Anja","family":"Bye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"6","key":"2025070923450426000_2025.07.07.25330991v1.1","doi-asserted-by":"crossref","first-page":"e183605","DOI":"10.1001\/jamanetworkopen.2018.3605","article-title":"Association of cardiorespiratory fitness with long-term mortality among adults undergoing exercise treadmill testing","volume":"1","year":"2018","journal-title":"JAMA Netw Open"},{"key":"2025070923450426000_2025.07.07.25330991v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2022.05.031"},{"issue":"20","key":"2025070923450426000_2025.07.07.25330991v1.3","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1093\/eurheartj\/ehy708","article-title":"Peak oxygen uptake and incident coronary heart disease in a healthy population: the HUNT Fitness Study","volume":"40","year":"2019","journal-title":"Eur Heart J"},{"key":"2025070923450426000_2025.07.07.25330991v1.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa011858"},{"issue":"2","key":"2025070923450426000_2025.07.07.25330991v1.5","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s10974-022-09636-y","article-title":"Determinants of maximal oxygen consumption","volume":"44","year":"2023","journal-title":"J Muscle Res Cell Motil"},{"key":"2025070923450426000_2025.07.07.25330991v1.6","doi-asserted-by":"publisher","DOI":"10.1111\/sms.12958"},{"key":"2025070923450426000_2025.07.07.25330991v1.7","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.167.2.211"},{"key":"2025070923450426000_2025.07.07.25330991v1.8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0113884"},{"key":"2025070923450426000_2025.07.07.25330991v1.9","doi-asserted-by":"publisher","DOI":"10.1249\/MSS.0000000000002951"},{"key":"2025070923450426000_2025.07.07.25330991v1.10","doi-asserted-by":"crossref","unstructured":"\u00c5svold BO , Langhammer A , Rehn TA , Kjelvik G , Gr\u00f8ntvedt TV , S\u00f8rgjerd EP , et al. Cohort Profile Update: The HUNT Study, Norway. Int J Epidemiol. 2022:1\u201312.","DOI":"10.1101\/2021.10.12.21264858"},{"key":"2025070923450426000_2025.07.07.25330991v1.11","doi-asserted-by":"crossref","unstructured":"Brumpton BM , Graham S , Surakka I , Skogholt AH , L\u00f8set M , Fritsche LG , et al. The HUNT study: A population-based cohort for genetic research. Cell Genomics. 2022;2(10).","DOI":"10.1016\/j.xgen.2022.100193"},{"key":"2025070923450426000_2025.07.07.25330991v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0579-z"},{"key":"2025070923450426000_2025.07.07.25330991v1.13","doi-asserted-by":"publisher","DOI":"10.1249\/MSS.0b013e31821d3f6f"},{"key":"2025070923450426000_2025.07.07.25330991v1.14","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.032432"},{"key":"2025070923450426000_2025.07.07.25330991v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09718-5"},{"key":"2025070923450426000_2025.07.07.25330991v1.16","first-page":"3","article-title":"A Package for Survival Analysis in R","volume":"3","year":"2022","journal-title":"R package version"},{"key":"2025070923450426000_2025.07.07.25330991v1.17","doi-asserted-by":"publisher","DOI":"10.1097\/PHM.0000000000001080"},{"key":"2025070923450426000_2025.07.07.25330991v1.18","doi-asserted-by":"crossref","unstructured":"Blackwell JEM , Doleman B , Herrod PJJ , Ricketts S , Phillips BE , Lund JN , et al. Short-Term (<8 wk) High-Intensity Interval Training in Diseased Cohorts. Med Sci Sports Exerc. 2018;50(9).","DOI":"10.1249\/MSS.0000000000001634"},{"key":"2025070923450426000_2025.07.07.25330991v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2008.03.017"},{"issue":"1","key":"2025070923450426000_2025.07.07.25330991v1.20","doi-asserted-by":"crossref","first-page":"55","DOI":"10.4103\/HEARTVIEWS.HEARTVIEWS_140_19","article-title":"Genetics in Cardiovascular Disease","volume":"21","year":"2020","journal-title":"Heart Views"},{"key":"2025070923450426000_2025.07.07.25330991v1.21","doi-asserted-by":"publisher","DOI":"10.2174\/1573403x09666131117170446"},{"key":"2025070923450426000_2025.07.07.25330991v1.22","doi-asserted-by":"publisher","DOI":"10.1007\/s11883-018-0711-4"},{"key":"2025070923450426000_2025.07.07.25330991v1.23","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwaa060"},{"key":"2025070923450426000_2025.07.07.25330991v1.24","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.147629"},{"key":"2025070923450426000_2025.07.07.25330991v1.25","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.675041"},{"key":"2025070923450426000_2025.07.07.25330991v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38234-w"},{"key":"2025070923450426000_2025.07.07.25330991v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmg.2017.07.016"},{"issue":"6","key":"2025070923450426000_2025.07.07.25330991v1.28","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1177\/2047487318754930","article-title":"The ambiguity of physical activity, exercise and atrial fibrillation","volume":"25","year":"2018","journal-title":"Eur J Prev Cardiol"},{"issue":"9","key":"2025070923450426000_2025.07.07.25330991v1.29","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1016\/j.hlc.2018.04.296","article-title":"Exercise and Atrial Fibrillation: Prevention or Causation?","volume":"27","year":"2018","journal-title":"Heart Lung Circ"},{"key":"2025070923450426000_2025.07.07.25330991v1.30","doi-asserted-by":"crossref","unstructured":"Nordeidet AN , Klevjer M , \u00d8vretveit K , Madssen E , Wisl\u00f8ff U , Brumpton BM , et al. Sex-specific and polygenic effects underlying resting heart rate and associated risk of cardiovascular disease. Eur J Prev Cardiol. 2024:zwae092.","DOI":"10.1093\/eurjpc\/zwae092"},{"key":"2025070923450426000_2025.07.07.25330991v1.31","doi-asserted-by":"crossref","unstructured":"Kjaergaard AD , Ellervik C , Jessen N , Lessard SJ . Cardiorespiratory fitness, body composition, diabetes, and longevity: a two-sample Mendelian randomization study. J Clin Endocrinol Metab. 2024.","DOI":"10.1210\/clinem\/dgae393"},{"key":"2025070923450426000_2025.07.07.25330991v1.32","doi-asserted-by":"publisher","DOI":"10.1093\/eurjpc\/zwad365"},{"key":"2025070923450426000_2025.07.07.25330991v1.33","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-020-00742-5"},{"key":"2025070923450426000_2025.07.07.25330991v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-0353-1"},{"key":"2025070923450426000_2025.07.07.25330991v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-94768-3"},{"key":"2025070923450426000_2025.07.07.25330991v1.36","doi-asserted-by":"publisher","DOI":"10.1007\/s40279-016-0655-1"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.07.07.25330991","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:40:07Z","timestamp":1768509607000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.07.07.25330991"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,7]]},"references-count":36,"URL":"https:\/\/doi.org\/10.1101\/2025.07.07.25330991","relation":{},"subject":[],"published":{"date-parts":[[2025,7,7]]},"subtype":"preprint"}}