{"doi":"10.64898/2026.01.07.26343583","title":"Prostate cancer risk prediction using polygenic hazard scores in Norwegian populations","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  More accurate risk prediction is needed for prostate cancer (PCa) to identify individuals at greatest risk of early-onset and clinically significant disease. Current screening paradigms, such as prostate-specific antigen screening, pose risks due to over-diagnosis and over-treatment of indolent disease. Polygenic hazard scores (PHS) can predict age-at-diagnosis of PCa and are being tested in prospective clinical screening trials. We assessed the performance of the latest PHS model for PCa (PHS601) in two Norwegian population-based cohort studies (N = 14,688 and N = 2,850) for predicting age-at-diagnosis of PCa and aggressive PCa. In a subset with whole-genome sequencing (N = 503), we directly compared PHS601-based stratification with screening for rare pathogenic variants. PHS601 effectively stratified participants by risk in both cohorts for both PCa (HR\n                  <jats:sub>80/20</jats:sub>\n                  = 5.74, 95% CI [5.06, 6.45] and 7.79 95% CI [5.70, 10.59]) and aggressive PCa (HR\n                  <jats:sub>80/20</jats:sub>\n                  = 4.60, 95% CI [3.19, 6.45] and 3.14 95% CI [1.49, 6.63]). Among individuals with whole-genome sequencing, the top 1.8% of PHS values conferred 8.8-fold higher risk than the median (HR = 8.78 [5.00, 14.40]), exceeding the risk associated with HOXB13 pathogenic variants (HR = 3.77 [1.75, 8.11]; 1.8% carrier frequency). This study provides the first external validation of PHS601 in independent Norwegian population-based cohorts and, within a WGS subset, a direct comparison with rare variant screening, supporting context-specific use of genotyping-based risk stratification in population screening.\n                </jats:p>","journal":null,"year":null,"id":640089,"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":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":983039,"name":"Bayram Cevdet Akdeniz","orcid":"0000-0002-9493-3105","position":1,"is_corresponding":false},{"id":12438,"name":"Sigve Nakken","orcid":"0000-0001-8468-2050","position":2,"is_corresponding":false},{"id":34326,"name":"Alexey Shadrin","orcid":"0000-0002-7467-250X","position":3,"is_corresponding":false},{"id":19608,"name":"Anders M. Dale","orcid":"0000-0002-6126-2966","position":4,"is_corresponding":false},{"id":52934,"name":"Ole A. Andreassen","orcid":"0000-0002-4461-3568","position":5,"is_corresponding":false},{"id":12355,"name":"Eivind Hovig","orcid":"0000-0002-9103-1077","position":6,"is_corresponding":false},{"id":360589,"name":"Tyler M. Seibert","orcid":"0000-0002-4089-7399","position":7,"is_corresponding":false},{"id":246428,"name":"Oleksandr Frei","orcid":"0000-0002-6427-2625","position":8,"is_corresponding":false},{"id":1663463,"name":"Andrew H. Morris","orcid":"0000-0002-3678-4498","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Prostate cancer risk prediction using polygenic hazard scores in Norwegian populations","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  More accurate risk prediction is needed for prostate cancer (PCa) to identify individuals at greatest risk of early-onset and clinically significant disease. Current screening paradigms, such as prostate-specific antigen screening, pose risks due to over-diagnosis and over-treatment of indolent disease. Polygenic hazard scores (PHS) can predict age-at-diagnosis of PCa and are being tested in prospective clinical screening trials. We assessed the performance of the latest PHS model for PCa (PHS601) in two Norwegian population-based cohort studies (N = 14,688 and N = 2,850) for predicting age-at-diagnosis of PCa and aggressive PCa. In a subset with whole-genome sequencing (N = 503), we directly compared PHS601-based stratification with screening for rare pathogenic variants. PHS601 effectively stratified participants by risk in both cohorts for both PCa (HR\n                  <jats:sub>80/20</jats:sub>\n                  = 5.74, 95% CI [5.06, 6.45] and 7.79 95% CI [5.70, 10.59]) and aggressive PCa (HR\n                  <jats:sub>80/20</jats:sub>\n                  = 4.60, 95% CI [3.19, 6.45] and 3.14 95% CI [1.49, 6.63]). Among individuals with whole-genome sequencing, the top 1.8% of PHS values conferred 8.8-fold higher risk than the median (HR = 8.78 [5.00, 14.40]), exceeding the risk associated with HOXB13 pathogenic variants (HR = 3.77 [1.75, 8.11]; 1.8% carrier frequency). This study provides the first external validation of PHS601 in independent Norwegian population-based cohorts and, within a WGS subset, a direct comparison with rare variant screening, supporting context-specific use of genotyping-based risk stratification in population screening.\n                </jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19910364","pmcid":null,"openalex_id":"https://openalex.org/W7119502255","authors":[],"funders":[{"funder_name":"The Research Council of Norway","grant_id":"324499","title":"Polygenic and psychosocial interplay in brain development across mental disorders"}],"total_grants":1,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":"cc-by","oa_locations":[{"url":"https://www.medrxiv.org/content/medrxiv/early/2026/01/08/2026.01.07.26343583.full.pdf","host_type":"repository"},{"url":"https://www.medrxiv.org/content/medrxiv/early/2026/01/08/2026.01.07.26343583.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.64898/2026.01.07.26343583","host_type":"publisher"},{"url":"https://doi.org/10.64898/2026.01.07.26343583","host_type":"repository"}],"fields_of_study":["Prostate Cancer Diagnosis and Treatment","Genetic Associations and Epidemiology","Genomics and Rare Diseases","03 medical and health sciences","0302 clinical medicine"],"mesh_terms":[],"keywords":["Norwegian","Prostate cancer","Polygenic risk score","Hazard ratio","Risk assessment","Prostate-specific antigen","Prospective cohort study"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-07T06:37:40.768200Z","pmid":null,"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":[]}