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In 353,118 average\u2010risk UK Biobank participants, we used family history\u2010stratified Cox models to estimate associations of sex and PRS with CRC incidence, metastasis, and CRC\u2010specific mortality. We translated risk differences into risk\u2010adapted initiation screening ages using both risk advancement period (RAP) and absolute 10\u2010year cumulative risk. Men had a higher risk of CRC compared to women, with HRs of 1.41 (95% CI, 1.33\u20131.50) for those without family history and 1.42 (95% CI, 1.26\u20131.61) for those with family history. For each one\u2010standard deviation (SD) increase in PRS, the risk was 1.49 times higher (95% CI, 1.45\u20131.53) in participants without a family history and 1.42 times higher (95% CI, 1.34\u20131.51) in those with a family history. The increase in PRS was associated with elevated risks of both metastatic CRC at diagnosis and CRC\u2010specific mortality, indicating delayed diagnosis in high\u2010PRS individuals and highlighting the potential benefit of earlier screening. Consequently, risk\u2010adapted initiation ages ranged from before 40\u2009years for men with a family history in the high\u2010PRS group to after 60\u2009years for women without a family history in the low\u2010PRS group. Our findings demonstrate that the integration of PRS, biological sex, and family history identifies substantial heterogeneity in CRC risk and risk\u2010adapted screening initiation ages.<\/jats:p>","DOI":"10.1002\/ijc.70774","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T11:56:50Z","timestamp":1791806210000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating Polygenic Risk Score, Sex, and Family History to Personalize the Initial Screening Age for Colorectal Cancer"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8632-4895","authenticated-orcid":false,"given":"Wen","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Health Statistics, School of Public Health Capital Medical University  Beijing China"},{"name":"Beijing Key Laboratory of Environment and Aging Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Liu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Macau  Macau SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxue","family":"Wang","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Macau  Macau SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Health Statistics, School of Public Health Capital Medical University  Beijing China"},{"name":"Beijing Key Laboratory of Environment and Aging Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Health Statistics, School of Public Health Capital Medical University  Beijing China"},{"name":"Beijing Key Laboratory of Environment and Aging Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7276-9044","authenticated-orcid":false,"given":"Fen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Health Statistics, School of Public Health Capital Medical University  Beijing China"},{"name":"Beijing Key Laboratory of Environment and Aging Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Primary Health Care Research, Department of Clinical Sciences Malm\u00f6 Lund University  Malm\u00f6 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5659-5045","authenticated-orcid":false,"given":"Deqiang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Health Statistics, School of Public Health Capital Medical University  Beijing China"},{"name":"Beijing Key Laboratory of Environment and Aging Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0324-9496","authenticated-orcid":false,"given":"Jianguang","family":"Ji","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Macau  Macau SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"key":"e_1_2_13_2_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray F.","year":"2024","journal-title":"CA: A Cancer Journal for Clinicians"},{"key":"e_1_2_13_3_1","unstructured":"Society AC \u201cSurvival Rates for Colorectal Cancer \u201d(2025)."},{"key":"e_1_2_13_4_1","doi-asserted-by":"crossref","DOI":"10.7326\/L24-0012","article-title":"Screening for Colorectal Cancer","volume":"177","author":"Patel S. 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