{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T22:13:43Z","timestamp":1790374423709,"version":"4.1.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,7,19]],"date-time":"2025-07-19T00:00:00Z","timestamp":1752883200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007155","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/T006927\/1"],"award-info":[{"award-number":["MR\/T006927\/1"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000406","name":"Motor Neurone Disease Association","doi-asserted-by":"publisher","award":["Thompson\/Jan20\/952-795"],"award-info":[{"award-number":["Thompson\/Jan20\/952-795"]}],"id":[{"id":"10.13039\/501100000406","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000406","name":"Motor Neurone Disease Association","doi-asserted-by":"publisher","award":["Thompson\/Apr23\/896-791"],"award-info":[{"award-number":["Thompson\/Apr23\/896-791"]}],"id":[{"id":"10.13039\/501100000406","id-type":"DOI","asserted-by":"publisher"}]},{"name":"My Name\u20195 Doddie Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The C9orf72 hexanucleotide repeat expansion (HRE) is the most common monogenetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neurodegenerative disease incidence in C9orf72 HRE carriers has been studied using cohorts from disease-affected families or by extrapolating from population disease incidence, potentially introducing bias.<\/jats:p>\n                  <jats:p>Age-specific cumulative incidence of ALS and dementia was estimated using Kaplan\u2013Meier and competing risk models in C9orf72 HRE carriers compared to matched controls in UK Biobank. Risk modification by UNC13A genotype was examined.<\/jats:p>\n                  <jats:p>Of 490 331 individuals with valid genetic data, 701 had &amp;gt;100 repeats in C9orf72 [median age 55 (interquartile range 48\u201362), follow-up 13.4 years (12.3\u201314.1)]. The cumulative incidence of ALS or dementia was 66% (95% confidence interval 57%\u201373%) by age 80 in C9orf72 HRE carriers versus 5.8% (4.5%\u20137.0%) in controls, or 58% (50%\u201364%) versus 5.1% (4.1%\u20136.4%), accounting for the competing risk of other-cause mortality. Forty-one per cent of dementia incidence accrued between age 75\u201380. C-allele homozygosity at rs12608932 in UNC13A increased ALS or dementia risk in C9orf72 HRE carriers [hazard ratio 1.81 (1.18\u20132.78)].<\/jats:p>\n                  <jats:p>C9orf72 HRE disease was incompletely penetrant in this population-based cohort, with risk modified by UNC13A genotype. This has implications for counselling at-risk individuals and modelling expected phenoconversion for prevention trials.<\/jats:p>","DOI":"10.1093\/brain\/awaf269","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T12:08:48Z","timestamp":1752754128000},"page":"3865-3871","source":"Crossref","is-referenced-by-count":15,"title":["Neurodegenerative disease in\n                    <i>C9orf72<\/i>\n                    repeat expansion carriers: population risk and effect of\n                    <i>UNC13A<\/i>"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5461-1742","authenticated-orcid":false,"given":"Jiali","family":"Gao","sequence":"first","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G L","family":"Douglas","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford OX3 9DU ,","place":["UK"]},{"name":"Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos V","family":"Chalitsios","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0146-1821","authenticated-orcid":false,"given":"Jakub","family":"Scaber","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5490-1697","authenticated-orcid":false,"given":"Kevin","family":"Talbot","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0267-3180","authenticated-orcid":false,"given":"Martin R","family":"Turner","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1063-3277","authenticated-orcid":false,"given":"Alexander G","family":"Thompson","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,19]]},"reference":[{"key":"2025110518444140800_awaf269-B1","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S1474-4422(12)70043-1","article-title":"Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study","volume":"11","author":"Majounie","year":"2012","journal-title":"Lancet Neurol."},{"key":"2025110518444140800_awaf269-B2","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/S1474-4422(12)70014-5","article-title":"Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: A population-based cohort study","volume":"11","author":"Byrne","year":"2012","journal-title":"Lancet Neurol"},{"key":"2025110518444140800_awaf269-B3","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1093\/brain\/awr361","article-title":"Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: Clinical, neuroanatomical and neuropathological features","volume":"135","author":"Mahoney","year":"2012","journal-title":"Brain"},{"key":"2025110518444140800_awaf269-B4","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1093\/brain\/awr366","article-title":"Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72","volume":"135","author":"Chi\u00f2","year":"2012","journal-title":"Brain"},{"key":"2025110518444140800_awaf269-B5","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1212\/WNL.0000000000003067","article-title":"Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population","volume":"87","author":"Umoh","year":"2016","journal-title":"Neurology"},{"key":"2025110518444140800_awaf269-B6","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1136\/jnnp-2020-325377","article-title":"Unravelling the clinical spectrum and the role of repeat length in C9ORF72 repeat expansions","volume":"92","author":"van der Ende","year":"2021","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"Pt 2","key":"2025110518444140800_awaf269-B7","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1093\/brain\/aws357","article-title":"C9orf72 repeat expansions are a rare genetic cause of parkinsonism","volume":"136","author":"Lesage","year":"2013","journal-title":"Brain."},{"key":"2025110518444140800_awaf269-B8","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1001\/archneurol.2012.2016","article-title":"Investigation of C9orf72 in 4 neurodegenerative disorders","volume":"69","author":"Xi","year":"2012","journal-title":"Arch Neurol."},{"key":"2025110518444140800_awaf269-B9","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.ajhg.2013.01.011","article-title":"Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population","volume":"92","author":"Beck","year":"2013","journal-title":"Am J Hum Genet."},{"key":"2025110518444140800_awaf269-B10","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s00401-013-1161-2","article-title":"Progressive amnestic dementia, hippocampal sclerosis, and mutation in C9ORF72","volume":"126","author":"Murray","year":"2013","journal-title":"Acta Neuropathol"},{"key":"2025110518444140800_awaf269-B11","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1136\/practneurol-2021-002989","article-title":"Genetic testing in motor neurone disease","volume":"22","author":"Dharmadasa","year":"2022","journal-title":"Pract Neurol"},{"key":"2025110518444140800_awaf269-B12","doi-asserted-by":"crossref","first-page":"e334339","DOI":"10.1136\/jnnp-2024-334339","article-title":"Guidance for clinical management of pathogenic variant carriers at elevated genetic risk for ALS\/FTD","volume":"96","author":"Benatar","year":"2025","journal-title":"J Neurol Neurosurg Psychiatry."},{"key":"2025110518444140800_awaf269-B13","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1038\/s41598-017-02364-1","article-title":"Age-related penetrance of the C9orf72 repeat expansion","volume":"7","author":"Murphy","year":"2017","journal-title":"Sci Rep"},{"key":"2025110518444140800_awaf269-B14","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1080\/21678421.2023.2272187","article-title":"Assessment of risk of ALS conferred by the GGGGCC hexanucleotide repeat expansion in C9orf72 among first-degree relatives of patients with ALS carrying the repeat expansion","volume":"25","author":"Van Wijk","year":"2024","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener."},{"key":"2025110518444140800_awaf269-B15","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1136\/jmg-2023-109580","article-title":"Reduced penetrance of gene variants causing amyotrophic lateral sclerosis","volume":"61","author":"Douglas","year":"2024","journal-title":"J Med Genet."},{"key":"2025110518444140800_awaf269-B16","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1038\/ng.442","article-title":"Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis","volume":"41","author":"Van Es","year":"2009","journal-title":"Nat Genet"},{"key":"2025110518444140800_awaf269-B17","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1002\/ana.24198","article-title":"C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: A genome-wide meta-analysis","volume":"76","author":"Diekstra","year":"2014","journal-title":"Ann Neurol"},{"key":"2025110518444140800_awaf269-B18","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41586-022-04436-3","article-title":"TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A","volume":"603","author":"Brown","year":"2022","journal-title":"Nature"},{"key":"2025110518444140800_awaf269-B19","doi-asserted-by":"crossref","first-page":"357.e1","DOI":"10.1016\/j.neurobiolaging.2012.07.016","article-title":"UNC13A influences survival in Italian amyotrophic lateral sclerosis patients: A population-based study","volume":"34","author":"Chi\u00f2","year":"2013","journal-title":"Neurobiol Aging"},{"key":"2025110518444140800_awaf269-B20","doi-asserted-by":"crossref","first-page":"e1001779","DOI":"10.1371\/journal.pmed.1001779","article-title":"UK Biobank: An open access resource for identifying the causes of a wide range of complex diseases of middle and old age","volume":"12","author":"Sudlow","year":"2015","journal-title":"PLoS Med."},{"key":"2025110518444140800_awaf269-B21","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1101\/gr.225672.117","article-title":"Detection of long repeat expansions from PCR-free whole-genome sequence data","volume":"27","author":"Dolzhenko","year":"2017","journal-title":"Genome Res"},{"key":"2025110518444140800_awaf269-B22","author":"QurAlis Corporation"},{"key":"2025110518444140800_awaf269-B23","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1038\/s41591-022-01942-9","article-title":"Temporal order of clinical and biomarker changes in familial frontotemporal dementia","volume":"28","author":"Staffaroni","year":"2022","journal-title":"Nat Med"},{"key":"2025110518444140800_awaf269-B24","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s00401-014-1251-9","article-title":"The widening spectrum of C9ORF72-related disease; genotype\/phenotype correlations and potential modifiers of clinical phenotype","volume":"127","author":"Cooper-Knock","year":"2014","journal-title":"Acta Neuropathol"},{"key":"2025110518444140800_awaf269-B25","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1007\/s10654-019-00499-1","article-title":"Identifying dementia outcomes in UK Biobank: A validation study of primary care, hospital admissions and mortality data","volume":"34","author":"Wilkinson","year":"2019","journal-title":"Eur J Epidemiol"},{"key":"2025110518444140800_awaf269-B26","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","article-title":"New insights into the genetic etiology of Alzheimer\u2019s disease and related dementias","volume":"54","author":"Bellenguez","year":"2022","journal-title":"Nat Genet"},{"key":"2025110518444140800_awaf269-B27","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1093\/aje\/kwx246","article-title":"Comparison of sociodemographic and health-related characteristics of UK Biobank participants with those of the general population","volume":"186","author":"Fry","year":"2017","journal-title":"Am J Epidemiol."},{"key":"2025110518444140800_awaf269-B28","volume-title":"Dementia UK: Update","author":"Prince","year":"2014","edition":"2nd ed"},{"key":"2025110518444140800_awaf269-B29","doi-asserted-by":"crossref","first-page":"101695","DOI":"10.1016\/j.eclinm.2022.101695","article-title":"Serum lipid traits and the risk of dementia: A cohort study of 254,575 women and 214,891 men in the UK Biobank","volume":"54","author":"Gong","year":"2022","journal-title":"EClinicalMedicine"},{"key":"2025110518444140800_awaf269-B30","doi-asserted-by":"crossref","first-page":"e0172639","DOI":"10.1371\/journal.pone.0172639","article-title":"Accuracy of routinely-collected healthcare data for identifying motor neurone disease cases: A systematic review","volume":"12","author":"Horrocks","year":"2017","journal-title":"PLoS One"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awaf269\/63802746\/awaf269.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/148\/11\/3865\/63802746\/awaf269.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/148\/11\/3865\/63802746\/awaf269.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T23:44:52Z","timestamp":1762386292000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/148\/11\/3865\/8208117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,19]]},"references-count":30,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,7,19]]},"published-print":{"date-parts":[[2025,11,4]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awaf269","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,11]]},"published":{"date-parts":[[2025,7,19]]}}}