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dc.contributor.authorSanchez-Juan, Pascual
dc.contributor.authorBishop, Matthew T
dc.contributor.authorKovacs, Gabor G
dc.contributor.authorCalero, Miguel 
dc.contributor.authorAulchenko, Yurii S
dc.contributor.authorLadogana, Anna
dc.contributor.authorBoyd, Alison
dc.contributor.authorLewis, Victoria
dc.contributor.authorPonto, Claudia
dc.contributor.authorCalero, Olga 
dc.contributor.authorPoleggi, Anna
dc.contributor.authorCarracedo, Ángel
dc.contributor.authorvan der Lee, Sven J
dc.contributor.authorStröbel, Thomas
dc.contributor.authorRivadeneira, Fernando
dc.contributor.authorHofman, Albert
dc.contributor.authorHaïk, Stéphane
dc.contributor.authorCombarros, Onofre
dc.contributor.authorBerciano, José
dc.contributor.authorUitterlinden, Andre G
dc.contributor.authorCollins, Steven J
dc.contributor.authorBudka, Herbert
dc.contributor.authorBrandel, Jean-Philippe
dc.contributor.authorLaplanche, Jean Louis
dc.contributor.authorPocchiari, Maurizio
dc.contributor.authorZerr, Inga
dc.contributor.authorKnight, Richard S G
dc.contributor.authorWill, Robert G
dc.contributor.authorvan Duijn, Cornelia M
dc.identifier.citationPLoS One. 2015 Apr 28;10(4):e0123654.es_ES
dc.description.abstractWe performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis.es_ES
dc.description.sponsorshipThis study was supported by: UK: the National CJD Research and Surveillance UK Unit is funded by the Department of Health and the Scottish Government Health Department. The National CJD Research and Surveillance Unit is funded by the Policy Research Programme in the Department of Health. Germany: This work was supported by a grant from the European Commission (Protecting the food chain from prions: shaping European priorities through basic and applied research (PRIORITY, N° 222887) Project number: FP7-KBBE-2007-2A). The study was performed within the recently established Clinical Dementia Center at the University Medical Center Göttingen and was partly supported by grants from the EU Joint Programme – Neurodegenerative Disease Research (JPND - DEMTEST "Biomarker based diagnosis of rapid progressive dementias optimization of diagnostic protocols", 01ED1201A). This study was funded by the Robert Koch Institute through funds from the Federal Ministry of Health (grant no. 1369-341). Italy: The Italian Registry of CJD and related disorders is funded by the Ministry of Health, National Centre for Disease Prevention and Control, Central Actions.This work was partly supported by grant from the EU Joint Programme – Neurodegenerative Disease Research (JPND-DEMTEST “Biomarker based diagnosis of rapid progressive dementias-optimization of diagnostic protocols”, 01ED1201A). The Netherlands: the generation and management of genome-wide association study (GWAS) genotype data for the Rotterdam Study is supported by the Netherlands Organization of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. YSA is supported by Russian Science Foundation (RSCF) grant 14-14-00313. Spain. PSJ was supported by a grant from FIS (PI12/02288) and JPND project DEMTEST (PI11/03028). AC is supported by PI13/01136 Acción Estratégica de Salud del Instituto de Salud Carlos III e INNOPHARMA. Australia: The Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR) is funded by the Commonwealth Department of Health. SJC is supported by a NHMRC Practitioner Fellowship (#APP1005816). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscriptes_ES
dc.publisherPublic Library of Science (PLOS) es_ES
dc.subject.meshPolymorphism, Single Nucleotidees_ES
dc.subject.meshCase-Control Studies es_ES
dc.subject.meshCreutzfeldt-Jakob Syndrome es_ES
dc.subject.meshGenome-Wide Association Study es_ES
dc.subject.meshGermany es_ES
dc.subject.meshHumans es_ES
dc.subject.meshNetherlands es_ES
dc.subject.meshPrion Proteins es_ES
dc.subject.meshPrions es_ES
dc.subject.meshReceptors, Metabotropic Glutamatees_ES
dc.subject.meshSignal Transduction es_ES
dc.subject.meshUnited Kingdom es_ES
dc.titleA genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease riskes_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderScottish Government
dc.contributor.funderUnión Europea. Comisión Europea. 7 Programa Marco 
dc.contributor.funderRobert Koch Institute
dc.contributor.funderFederal Ministry for Health (Alemania) 
dc.contributor.funderMinistero della Salute (Italia) 
dc.contributor.funderDutch Research Council (Holanda) 
dc.contributor.funderNational Foundation for the Elderly (Holanda)
dc.contributor.funderErasmus University Rotterdam (Países Bajos) 
dc.contributor.funderNetherlands Organisation for Health Research and Development 
dc.contributor.funderMinistery of Education, Culture and Science (Holanda) 
dc.contributor.funderUnión Europea. Comisión Europea 
dc.contributor.funderRussian Science Foundation
dc.contributor.funderInstituto de salud Carlos III 
dc.contributor.funderAustralian National Creutzfeldt-Jakob Disease Registry
dc.contributor.funderCommonwealth Fund
dc.contributor.funderNational Health and Medical Research Council (Australia) 
dc.identifier.journalPloS onees_ES
dc.repisalud.centroISCIII::Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)es_ES
dc.rights.accessRightsopen accesses_ES
dc.relation.projectFISinfo:fis/Instituto de Salud Carlos III/null/null/Subprograma de proyectos de investigacion en salud (AES 2012) (2012)/PI12/02288
dc.relation.projectFISinfo:fis/Instituto de Salud Carlos III/null/null/Subprograma de proyectos de investigación en salud (AES 2011) Europeos (2011)/PI11/03028
dc.relation.projectFISinfo:fis/Instituto de Salud Carlos III/null/null/Subprograma de proyectos de investigacion en salud (AES 2013) (2013)/PI13/01136

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Atribución 4.0 Internacional
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