{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:32:34Z","timestamp":1787164354356,"version":"build-2736575974"},"reference-count":88,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T00:00:00Z","timestamp":1737936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["BOF 49758"],"award-info":[{"award-number":["BOF 49758"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007660","name":"University of Antwerp","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007660","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Brein Instituut"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Prions are assemblies of misfolded prion protein that cause several fatal and transmissible neurodegenerative diseases, with the most common phenotype in humans being sporadic Creutzfeldt-Jakob disease (sCJD). Aside from variation of the prion protein itself, molecular risk factors are not well understood. Prion and prion-like mechanisms are thought to underpin common neurodegenerative disorders meaning that the elucidation of mechanisms could have broad relevance. Herein we sought to further develop our understanding of the factors that confer risk of sCJD using a systematic gene prioritization and functional interpretation pipeline based on multiomic integrative analyses.<\/jats:p>\n                  <jats:p>We integrated the published sCJD genome-wide association study summary statistics with publicly available bulk brain and brain cell type gene and protein expression datasets. We performed multiple transcriptome and proteome-wide association studies and Bayesian genetic colocalization analyses between sCJD risk association signals and multiple brain molecular quantitative trait loci signals. We then applied our systematic gene prioritization pipeline to the obtained results and nominated prioritized sCJD risk genes with risk-associated molecular mechanisms in a transcriptome and proteome-wide manner.<\/jats:p>\n                  <jats:p>Genetic upregulation of both gene and protein expression of syntaxin-6 (STX6) in the brain was associated with sCJD risk in multiple datasets, with a risk-associated gene expression regulation specific to oligodendrocytes. Similarly, increased gene and protein expression of protein disulfide isomerase family A member 4 (PDIA4), involved in the unfolded protein response, was linked to increased disease risk, particularly in excitatory neurons. Protein expression of mesencephalic astrocyte derived neurotrophic factor (MANF), involved in protection against endoplasmic reticulum stress and sulfatide binding (linking to the enzyme in the final step of sulfatide synthesis, encoded by sCJD risk gene GAL3ST1), was identified as protective against sCJD. In total 32 genes were prioritized into two tiers based on the level of evidence and confidence for further studies.<\/jats:p>\n                  <jats:p>This study provides insights into the genetically-associated molecular mechanisms underlying sCJD susceptibility and prioritizes several specific hypotheses for exploration beyond the prion protein itself, as well as beyond the previously highlighted sCJD risk loci, through the newly prioritized sCJD risk genes and mechanisms. These findings highlight the importance of glial cells, sulfatides and the excitatory neuron unfolded protein response in sCJD pathogenesis.<\/jats:p>","DOI":"10.1093\/brain\/awaf032","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T15:21:52Z","timestamp":1737732112000},"page":"3350-3363","source":"Crossref","is-referenced-by-count":11,"title":["Multiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes"],"prefix":"10.1093","volume":"148","author":[{"given":"Fahri","family":"K\u00fc\u00e7\u00fckali","sequence":"first","affiliation":[{"name":"Complex Genetics of Alzheimer\u2019s Disease group, VIB Center for Molecular Neurology, VIB , Antwerp 2610 ,","place":["Belgium"]},{"name":"Department of Biomedical Sciences, University of Antwerp , Antwerp 2610 ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Hill","sequence":"additional","affiliation":[{"name":"Medical Research Council Prion Unit, University College London Institute of Prion Diseases , London W1W 7FF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tijs","family":"Watzeels","sequence":"additional","affiliation":[{"name":"Complex Genetics of Alzheimer\u2019s Disease group, VIB Center for Molecular Neurology, VIB , Antwerp 2610 ,","place":["Belgium"]},{"name":"Department of Biomedical Sciences, University of Antwerp , Antwerp 2610 ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Hummerich","sequence":"additional","affiliation":[{"name":"Medical Research Council Prion Unit, University College London Institute of Prion Diseases , London W1W 7FF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Campbell","sequence":"additional","affiliation":[{"name":"Medical Research Council Prion Unit, University College London Institute of Prion Diseases , London W1W 7FF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Darwent","sequence":"additional","affiliation":[{"name":"Medical Research Council Prion Unit, University College London Institute of Prion Diseases , London W1W 7FF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Collins","sequence":"additional","affiliation":[{"name":"Australian National Creutzfeldt-Jakob Disease Registry, The Florey and Department of Medicine (RMH), The University of Melbourne , Melbourne, Victoria 3010 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Stehmann","sequence":"additional","affiliation":[{"name":"Australian National Creutzfeldt-Jakob Disease Registry, The Florey and Department of Medicine (RMH), The University of Melbourne , Melbourne, Victoria 3010 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3841-5511","authenticated-orcid":false,"given":"Gabor G","family":"Kovacs","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Disease, University of Toronto , Toronto, ON M5S 1A8 ,","place":["Canada"]},{"name":"Krembil Brain Institute, University Health Network , Toronto, ON M5T 0S8 ,","place":["Canada"]},{"name":"Laboratory Medicine Program, University Health Network , Toronto, ON M5G 2C4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D","family":"Geschwind","sequence":"additional","affiliation":[{"name":"UCSF Memory and Aging Center, Department of Neurology, University of California , San Francisco, CA 94158 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Frontzek","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University of Z\u00fcrich , 8006 Z\u00fcrich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert","family":"Budka","sequence":"additional","affiliation":[{"name":"Austrian Reference Centre for Human Prion Diseases, Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University Vienna , 1090 Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Gelpi","sequence":"additional","affiliation":[{"name":"Austrian Reference Centre for Human Prion Diseases, Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University Vienna , 1090 Vienna 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M","family":"van Duijn","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Erasmus Medical Centre , 3000 CA Rotterdam ,","place":["The Netherlands"]},{"name":"Nuffield Department of Population Health, University of Oxford , Oxford OX3 7LF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel P","family":"Liberski","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology and Neuropathology, Medical University of Lodz , Lodz 92-215 ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Calero","sequence":"additional","affiliation":[{"name":"Chronic Disease Programme (UFIEC) and Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid 28029, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6081-8037","authenticated-orcid":false,"given":"Pascual","family":"Sanchez-Juan","sequence":"additional","affiliation":[{"name":"Reina Sofia Alzheimer Center, CIEN Foundation, ISCIII, Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Bouaziz-Amar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Lariboisi\u00e8re Hospital, GHU AP-HP Nord, University of Paris Cit\u00e9 , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Louis","family":"Laplanche","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Lariboisi\u00e8re Hospital, GHU AP-HP Nord, University of Paris Cit\u00e9 , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Ha\u00efk","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, CNRS UMR 7225, Institut du Cerveau et de la Moelle \u00e9pini\u00e8re, ICM , Paris 75010 ,","place":["France"]},{"name":"Cellule nationale de r\u00e9f\u00e9rence des maladies de Creutzfeldt-Jakob, AP-HP, University Hospital Piti\u00e9-Salp\u00eatri\u00e8re , Paris 75010 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Phillipe","family":"Brandel","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, CNRS UMR 7225, Institut du Cerveau et de la Moelle \u00e9pini\u00e8re, ICM , Paris 75010 ,","place":["France"]},{"name":"Cellule nationale de r\u00e9f\u00e9rence des maladies de Creutzfeldt-Jakob, AP-HP, University Hospital Piti\u00e9-Salp\u00eatri\u00e8re , Paris 75010 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Mammana","sequence":"additional","affiliation":[{"name":"IRCCS, Istituto delle Scienze Neurologiche di Bologna , Bologna 40139 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1631-1439","authenticated-orcid":false,"given":"Sabina","family":"Capellari","sequence":"additional","affiliation":[{"name":"IRCCS, Istituto delle Scienze Neurologiche di Bologna , Bologna 40139 ,","place":["Italy"]},{"name":"Department of Biomedical and Neuromotor Sciences, University of Bologna , Bologna 40138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Poleggi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Istituto Superiore di Sanit\u00e0 , Roma 00161 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ladogana","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Istituto Superiore di Sanit\u00e0 , Roma 00161 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorina","family":"Tiple","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Istituto Superiore di Sanit\u00e0 , Roma 00161 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saima","family":"Zafar","sequence":"additional","affiliation":[{"name":"University Medical Center G\u00f6ttingen, Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, 37075 G\u00f6ttingen ,","place":["Germany"]},{"name":"Biomedical Engineering and Sciences Department, School of Mechanical and Manufacturing Engineering, National University of Sciences and Technology , Islamabad 44000 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L\u00f8bner","family":"Lund","sequence":"additional","affiliation":[{"name":"Danish Reference Center for Prion Diseases, Department of Pathology, Copenhagen University Hospital, Rigshospitalet , Copenhagen 2100 ,","place":["Denmark"]},{"name":"Department of Clinical Medicine, University of Copenhagen , Copenhagen 2100 ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Glisic","sequence":"additional","affiliation":[{"name":"National Prion Disease Pathology Surveillance Center, Case Western Reserve University , Cleveland, OH 44106 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9444-9524","authenticated-orcid":false,"given":"Piero","family":"Parchi","sequence":"additional","affiliation":[{"name":"IRCCS, Istituto delle Scienze Neurologiche di Bologna , Bologna 40139 ,","place":["Italy"]},{"name":"Department of Biomedical and Neuromotor Sciences, University of Bologna , Bologna 40138 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Hermann","sequence":"additional","affiliation":[{"name":"University Medical Center G\u00f6ttingen, Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, 37075 G\u00f6ttingen ,","place":["Germany"]},{"name":"German Center for Neurodegenerative Diseases (DZNE), 37075 G\u00f6ttingen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inga","family":"Zerr","sequence":"additional","affiliation":[{"name":"University Medical Center G\u00f6ttingen, Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, 37075 G\u00f6ttingen ,","place":["Germany"]},{"name":"German Center for Neurodegenerative Diseases (DZNE), 37075 G\u00f6ttingen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Safar","sequence":"additional","affiliation":[{"name":"National Prion Disease Pathology Surveillance Center, Case Western Reserve University , Cleveland, OH 44106 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierluigi","family":"Gambetti","sequence":"additional","affiliation":[{"name":"National Prion Disease Pathology Surveillance Center, Case Western Reserve University , Cleveland, OH 44106 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian S","family":"Appleby","sequence":"additional","affiliation":[{"name":"National Prion Disease Pathology Surveillance Center, Case Western Reserve University , Cleveland, OH 44106 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Collinge","sequence":"additional","affiliation":[{"name":"Medical Research Council Prion Unit, University College London Institute of Prion Diseases , London W1W 7FF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristel","family":"Sleegers","sequence":"additional","affiliation":[{"name":"Complex Genetics of Alzheimer\u2019s Disease group, VIB Center for Molecular Neurology, VIB , Antwerp 2610 ,","place":["Belgium"]},{"name":"Department of Biomedical Sciences, University of Antwerp , Antwerp 2610 ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Mead","sequence":"additional","affiliation":[{"name":"Medical Research Council Prion Unit, University College London Institute of Prion Diseases , London W1W 7FF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,1,27]]},"reference":[{"key":"2025090219574828500_awaf032-B1","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/s41589-022-01229-7","article-title":"A 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humans and animals: Their causes and molecular basis","volume":"24","author":"Collinge","year":"2001","journal-title":"Annu Rev Neurosci"},{"key":"2025090219574828500_awaf032-B6","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1136\/jnnp-2012-304820","article-title":"Intensity of human prion disease surveillance predicts observed disease incidence","volume":"84","author":"Genevieve","year":"2013","journal-title":"J Neurol, Neurosurg Psychiatry"},{"key":"2025090219574828500_awaf032-B7","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/S1474-4422(22)00082-5","article-title":"Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt-Jakob disease: Evaluation of a first-in-human treatment programme","volume":"21","author":"Mead","year":"2022","journal-title":"Lancet Neurol"},{"key":"2025090219574828500_awaf032-B8","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/S1474-4422(20)30273-8","article-title":"Identification of novel risk loci and 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