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We estimated hemochromatosis\u2010genotype associations with clinically diagnosed musculoskeletal outcomes and joint replacement surgeries in the UK Biobank community cohort. A total of 451,143 European ancestry participants (40 to 70\u2009years at baseline) were followed in hospital records (mean 11.5\u2010years). Cox proportional hazards models estimated\n                    <jats:italic>HFE<\/jats:italic>\n                    p.C282Y and p.H63D associations with incident outcomes. Male p.C282Y homozygotes (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20091294) had increased incidence of osteoarthritis (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200952, hazard ratio [HR]: 2.12 [95% confidence interval, CI: 1.61 to 2.80];\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20098.8\u2009\u00d7\u200910\n                    <jats:sup>\u22128<\/jats:sup>\n                    ), hip replacement (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200988, HR: 1.84 [95% CI: 1.49 to 2.27];\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20091.6\u2009\u00d7\u200910\n                    <jats:sup>\u22128<\/jats:sup>\n                    ), knee replacement (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200961, HR: 1.54 [95% CI: 1.20 to 1.98];\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20098.4\u2009\u00d7\u200910\n                    <jats:sup>\u22124<\/jats:sup>\n                    ), and ankle and shoulder replacement, compared to males with no\n                    <jats:italic>HFE<\/jats:italic>\n                    mutations. Cumulative incidence analysis, using Kaplan\u2013Meier lifetable probabilities demonstrated 10.4% of male homozygotes were projected to develop osteoarthritis and 15.5% to have hip replacements by age 75, versus 5.0% and 8.7% respectively without mutations. Male p.C282Y homozygotes also had increased incidence of femoral fractures (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200915, HR: 1.72 [95% CI: 1.03 to 2.87];\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.04) and osteoporosis (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200921, HR: 1.71 [95% CI: 1.11 to 2.64];\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.02), although the latter association was limited to those with liver fibrosis\/cirrhosis diagnoses. Female p.C282Y homozygotes had increased incidence of osteoarthritis only (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200957, HR: 1.46, [95% CI: 1.12 to 1.89];\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.01). Male p.C282Y\/p.H63D compound heterozygotes experienced a modest increased risk of hip replacements (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009234, HR: 1.17 [95% CI: 1.02 to 1.33],\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.02), but this did not pass multiple testing corrections. In this large community cohort, the p.C282Y homozygote genotype was associated with substantial excess musculoskeletal morbidity in males. Wider\n                    <jats:italic>HFE<\/jats:italic>\n                    genotype testing may be justified, including in orthopedic clinics serving higher\n                    <jats:italic>HFE<\/jats:italic>\n                    variant prevalence populations. \u00a9 2023 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10794","type":"journal-article","created":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T04:19:58Z","timestamp":1689653998000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Hemochromatosis Genetic Variants and Musculoskeletal Outcomes: 11.5\u2010Year Follow\u2010Up in the\n                    <scp>UK<\/scp>\n                    Biobank Cohort Study"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8942-8449","authenticated-orcid":false,"given":"Lucy R.","family":"Banfield","sequence":"first","affiliation":[{"name":"The Department of Health and Care Professions, Faculty of Health and Life Sciences University of Exeter  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7360-0926","authenticated-orcid":false,"given":"Karen M.","family":"Knapp","sequence":"additional","affiliation":[{"name":"The Department of Health and Care Professions, Faculty of Health and Life Sciences University of Exeter  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3332-8454","authenticated-orcid":false,"given":"Luke C.","family":"Pilling","sequence":"additional","affiliation":[{"name":"Epidemiology and Public Health Group, The Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences University of Exeter  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0170-3838","authenticated-orcid":false,"given":"David","family":"Melzer","sequence":"additional","affiliation":[{"name":"Epidemiology and Public Health Group, The Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences University of Exeter  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4919-9068","authenticated-orcid":false,"given":"Janice L.","family":"Atkins","sequence":"additional","affiliation":[{"name":"Epidemiology and Public Health Group, The Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences University of Exeter  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,7,18]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3399\/bjgp13X668410"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k5222"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.21566"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3109\/03009742.2016.1155645"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.21883"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-020-00658-7"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-008-0701-4"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01623396"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/8756-3282(92)90086-C"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.100234"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2008.03874.x"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001779"},{"key":"e_1_2_11_14_1","volume-title":"UK Biobank: Protocol for a Large\u2010Scale Prospective Epidemiological Resource","author":"Collins R.","year":"2007"},{"issue":"9","key":"e_1_2_11_15_1","first-page":"1809","article-title":"Bone and joint involvement in genetic hemochromatosis: role of cirrhosis and iron overload","volume":"24","author":"Sinigaglia L","year":"1997","journal-title":"J Rheumatol"},{"key":"e_1_2_11_16_1","unstructured":"ROS vitamin D and bone health guideline.Independent professional body guideline | Guidelines; 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