2024-03-28T17:18:38Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/154682023-02-09T02:00:39Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_2109com_20.500.12105_2052col_20.500.12105_16970col_20.500.12105_2110
Repisalud
author
Sanchez-Juan, Pascual
author
Bishop, Matthew T
author
Kovacs, Gabor G
author
Calero, Miguel
author
Aulchenko, Yurii S
author
Ladogana, Anna
author
Boyd, Alison
author
Lewis, Victoria
author
Ponto, Claudia
author
Calero, Olga
author
Poleggi, Anna
author
Carracedo, Ángel
author
van der Lee, Sven J
author
Ströbel, Thomas
author
Rivadeneira, Fernando
author
Hofman, Albert
author
Haïk, Stéphane
author
Combarros, Onofre
author
Berciano, José
author
Uitterlinden, Andre G
author
Collins, Steven J
author
Budka, Herbert
author
Brandel, Jean-Philippe
author
Laplanche, Jean Louis
author
Pocchiari, Maurizio
author
Zerr, Inga
author
Knight, Richard S G
author
Will, Robert G
author
van Duijn, Cornelia M
funder
Scottish Government
funder
Unión Europea. Comisión Europea. 7 Programa Marco
funder
Robert Koch Institute
funder
Federal Ministry for Health (Alemania)
funder
Ministero della Salute (Italia)
funder
Dutch Research Council (Holanda)
funder
National Foundation for the Elderly (Holanda)
funder
Erasmus University Rotterdam (Países Bajos)
funder
Netherlands Organisation for Health Research and Development
funder
Ministery of Education, Culture and Science (Holanda)
funder
Unión Europea. Comisión Europea
funder
Russian Science Foundation
funder
Instituto de salud Carlos III
funder
Australian National Creutzfeldt-Jakob Disease Registry
funder
Commonwealth Fund
funder
National Health and Medical Research Council (Australia)
2023-02-08T12:39:47Z
2023-02-08T12:39:47Z
2015-04
PLoS One. 2015 Apr 28;10(4):e0123654.
http://hdl.handle.net/20.500.12105/15468
25918841
10.1371/journal.pone.0123654
1932-6203
PloS one
We 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.
eng
A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk
journal article
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URL
https://repisalud.isciii.es/bitstream/20.500.12105/15468/1/GenomeWideAssociationStudy_2015.pdf
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https://repisalud.isciii.es/bitstream/20.500.12105/15468/5/GenomeWideAssociationStudy_2015.pdf.txt
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GenomeWideAssociationStudy_2015.pdf.txt