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Little is known about genetic determinants of fatigue, especially in prostate cancer (PCa). This study aims to identify SNPs associated with long-term fatigue in a prospective cohort of PCa patients. A genome-wide association study was conducted in non-metastatic PCa patients treated with radiotherapy in 7 European countries and the USA. A total of 1,381 men recorded fatigue using the EORTC QLQ-C30 and 877 men additionally completed the Multidimensional Fatigue Inventory (MFI) up to two years post-radiotherapy. Clinically important fatigue is defined for the EORTC QLQ-C30 based on the proposed threshold as scores \u226539 and for the MFI as scores \u226575\n                    <jats:sup>th<\/jats:sup>\n                    percentile in the general German male population aged \u226560 years. Regression models adjusted for demographic, disease- and treatment-specific characteristics examine SNPs associated with clinically important fatigue. Differential gene expressions are explored using expression quantitative trait analysis. rs142212041 located in the\n                    <jats:italic>ACTR3\/CBWD2<\/jats:italic>\n                    gene region is significantly associated (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20093\u00d710\n                    <jats:sup>-8<\/jats:sup>\n                    ) with long-term physical fatigue in 643 men without physical fatigue pre-radiotherapy. Several potential risk loci (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20095\u00d710\n                    <jats:sup>-6<\/jats:sup>\n                    ) are identified for distinct fatigue phenotypes. Gene expression differences are observed for\n                    <jats:italic>ACTR3<\/jats:italic>\n                    and\n                    <jats:italic>CBWD2<\/jats:italic>\n                    , although not significant after correction for multiple testing. The results emphasise the multidimensionality of fatigue and suggest a plausible biological mechanism in fatigue pathophysiology, previously discussed for myalgic encephalomyelitis\/chronic fatigue syndrome, which might be a potential intervention target.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-72041-3","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T13:26:04Z","timestamp":1776864364000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic determinants of fatigue up to 2 years after radiotherapy in prostate cancer patients"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6650-6045","authenticated-orcid":false,"given":"Philipp","family":"Heumann","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7822-6726","authenticated-orcid":false,"given":"Miguel E.","family":"Aguado-Barrera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harkeran K.","family":"Jandu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Azria","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik","family":"Briers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4122-2323","authenticated-orcid":false,"given":"Ren\u00e9e","family":"Bultijnck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenny","family":"Chang-Claude","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ananya","family":"Choudhury","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6651-7166","authenticated-orcid":false,"given":"Alison M.","family":"Dunning","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Fachal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia","family":"Fuentes-R\u00edos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9773-4590","authenticated-orcid":false,"given":"Antonio","family":"G\u00f3mez-Caama\u00f1o","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1711-6101","authenticated-orcid":false,"given":"Sara","family":"Guti\u00e9rrez-Enr\u00edquez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3751-3929","authenticated-orcid":false,"given":"Rudolf","family":"Kaaks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah L.","family":"Kerns","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8746-2691","authenticated-orcid":false,"given":"Maarten","family":"Lambrecht","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Camilo Rosas","family":"Romero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barry S.","family":"Rosenstein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"De Ruysscher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2095-2426","authenticated-orcid":false,"given":"Martina E.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8771-8124","authenticated-orcid":false,"given":"Elena","family":"Sperk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hilary","family":"Stobart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. 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Grant\/Research Funding from: Cancer Research UK Research, as PIE: Oct 2021 to March 2028; NIHR Research, as PIE: Dec 2023 to Sept 2030; Prostate Cancer UK Research, as PIE: May 2022 to April 2029; Elekta AB Research, as PIE: Jan 2019 to Jan 2029; Medical Research Council (MRC) Research, as PIE: 2018 ongoing; Astex Pharmaceuticals, Joint Lead applicant: Oct 2021 to Aug 2026; Yorkshire Cancer Research, YCR Research Award, Co-applicant: Aug 2022 to Nov 2030 Honoraria for single events around educational talks for commercial organisations: Astra Zeneca: 2023 October to 2025; Merck: 01\/2023 - November 2025. DDR: No financial or non-financial competing interests as defined by Nature Portfolio or other interests that might be perceived to influence the interpretation of the article. AstraZeneca Research grant\/ support\/ Advisory Board: Institutional financial interests (no personal financial interests) BMS Research grant\/ support\/ Advisory Board: Institutional financial interests (no personal financial interests) Beigene Research grant\/ support\/ Advisory Board: Institutional financial interests (no personal financial interests) Philips Research grant\/ support\/ Advisory Board: Institutional financial interests (no personal financial interests) Olink Research grant\/ support\/ Advisory Board: Institutional financial interests (no personal financial interests) Eli-Lilly Advisory Board: Institutional financial interests (no personal financial interests) Pfizer Support: Institutional financial interests (no personal financial interests). The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3703"}}