{"doi":"10.1101/2025.07.07.25330991","title":"Polygenic prediction of cardiorespiratory fitness: The HUNT Study","abstract":"Abstract Background 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 PGS ) and assess its associations with cardiovascular disease (CVD) and all-cause mortality. We hypothesized that the CRF PGS would demonstrate similar cardioprotective benefits as the CRF phenotype. Methods Effect estimates from a genome-wide association study on directly measured CRF in the Trøndelag Health Study (HUNT; n = 4 525) were used in a Bayesian regression framework to develop multiple PGSs in an independent cohort from the UK Biobank ( n = 65 165). The top performing score was applied in the HUNT target cohort, excluding the discovery sample ( n = 82 109). Results 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·kg -1 ·min -1 between the bottom and top decile of the CRF PGS . Moreover, a high CRF PGS demonstrated cardioprotective effects, with reduced risk for CVD, myocardial infarction, hypertension, and all-cause mortality. We also found that the CRF PGS predisposed to lower risk of heart failure and hypertrophic cardiomyopathy in women. Conclusion 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.","journal":"medRxiv","year":2025,"id":569859,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9643,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":873766,"name":"Marie Klevjer","orcid":"0000-0001-8372-276X","position":1,"is_corresponding":false},{"id":50532,"name":"Ben Brumpton","orcid":"0000-0002-3058-1059","position":2,"is_corresponding":false},{"id":467736,"name":"Ulrik Wisløff","orcid":"0000-0002-7211-3587","position":3,"is_corresponding":false},{"id":262547,"name":"Kristian Hveem","orcid":"0000-0001-8157-9744","position":4,"is_corresponding":false},{"id":873768,"name":"Anja Bye","orcid":"0000-0003-1259-5542","position":5,"is_corresponding":false},{"id":1069758,"name":"Karsten Øvretveit","orcid":"0000-0002-5528-0674","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:57:03.510013Z","pmid":"40672480","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}