{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T05:53:50Z","timestamp":1781762030246,"version":"3.54.5"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T00:00:00Z","timestamp":1721952000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_UU_00024\/1"],"award-info":[{"award-number":["MC_UU_00024\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_UU_00024\/1"],"award-info":[{"award-number":["MC_UU_00024\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5\u20139 (months)) was available in 3,773 and age at onset (median:67, IQR:61\u201373 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10\n                    <jats:sup>-36<\/jats:sup>\n                    , beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10\n                    <jats:sup>-67<\/jats:sup>\n                    , beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the\n                    <jats:italic>HS6ST3<\/jats:italic>\n                    gene was significant (pvalue = 1.93 x 10\n                    <jats:sup>\u22126<\/jats:sup>\n                    ) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants,\n                    <jats:italic>PRNP<\/jats:italic>\n                    codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0304528","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T13:40:59Z","timestamp":1722001259000},"page":"e0304528","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Genome wide association study of clinical duration and age at onset of sporadic CJD"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9654-8174","authenticated-orcid":true,"given":"Holger","family":"Hummerich","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Speedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Darwent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0031-0407","authenticated-orcid":true,"given":"Elizabeth","family":"Hill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8282-9151","authenticated-orcid":true,"given":"Christiane","family":"Stehmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabor 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P.","family":"Liberski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Calero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascual","family":"Sanchez-Juan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Bouaziz-Amar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Louis","family":"Laplanche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Ha\u00efk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Phillipe","family":"Brandel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Mammana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Capellari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Poleggi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ladogana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7269-2486","authenticated-orcid":true,"given":"Maurizio","family":"Pocchiari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saima","family":"Zafar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8108-5955","authenticated-orcid":true,"given":"Stephanie","family":"Booth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard 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Li","year":"2023","journal-title":"Alzheimers Dement"},{"issue":"6","key":"pone.0304528.ref039","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1002\/mds.27659","article-title":"Parkinson\u2019s disease age at onset genome-wide association study: Defining heritability, genetic loci, and \u03b1-synuclein mechanisms","volume":"34","author":"C Blauwendraat","year":"2019","journal-title":"Mov Disord"},{"issue":"6","key":"pone.0304528.ref040","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/s41582-021-00488-7","article-title":"The importance of ongoing international surveillance for Creutzfeldt-Jakob disease.","volume":"17","author":"N Watson","year":"2021","journal-title":"Nat Rev Neurol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0304528","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T13:41:31Z","timestamp":1722001291000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0304528"}},"subtitle":[],"editor":[{"given":"Gianluigi","family":"Zanusso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,7,26]]},"references-count":40,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7,26]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0304528","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.10.17.23297050","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,26]]}}}