Home > Publications Database > A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk. > print

001     137909
005     20240321220334.0
024 7 _ |a 10.1371/journal.pone.0123654
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037 _ _ |a DZNE-2020-04231
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Sanchez-Juan, Pascual
|b 0
245 _ _ |a A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.
260 _ _ |a San Francisco, California, US
|c 2014
|b PLOS
264 _ 1 |3 online
|2 Crossref
|b Public Library of Science (PLoS)
|c 2015-04-28
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
536 _ _ |a 344 - Clinical and Health Care Research (POF3-344)
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542 _ _ |i 2015-04-28
|2 Crossref
|u http://creativecommons.org/licenses/by/4.0/
588 _ _ |a Dataset connected to CrossRef, PubMed,
650 _ 7 |a PRNP protein, human
|2 NLM Chemicals
650 _ 7 |a Prion Proteins
|2 NLM Chemicals
650 _ 7 |a Prions
|2 NLM Chemicals
650 _ 7 |a Receptors, Metabotropic Glutamate
|2 NLM Chemicals
650 _ 7 |a metabotropic glutamate receptor 8
|2 NLM Chemicals
650 _ 2 |a Case-Control Studies
|2 MeSH
650 _ 2 |a Creutzfeldt-Jakob Syndrome: genetics
|2 MeSH
650 _ 2 |a Genome-Wide Association Study: methods
|2 MeSH
650 _ 2 |a Germany
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Netherlands
|2 MeSH
650 _ 2 |a Polymorphism, Single Nucleotide
|2 MeSH
650 _ 2 |a Prion Proteins
|2 MeSH
650 _ 2 |a Prions: genetics
|2 MeSH
650 _ 2 |a Receptors, Metabotropic Glutamate: genetics
|2 MeSH
650 _ 2 |a Signal Transduction
|2 MeSH
650 _ 2 |a United Kingdom
|2 MeSH
700 1 _ |a Bishop, Matthew T
|b 1
700 1 _ |a Kovacs, Gabor G
|b 2
700 1 _ |a Calero, Miguel
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700 1 _ |a Aulchenko, Yurii S
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700 1 _ |a Ladogana, Anna
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700 1 _ |a Boyd, Alison
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700 1 _ |a Lewis, Victoria
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700 1 _ |a Carracedo, Ángel
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700 1 _ |a van der Lee, Sven J
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700 1 _ |a Ströbel, Thomas
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700 1 _ |a Rivadeneira, Fernando
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700 1 _ |a Hofman, Albert
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700 1 _ |a Haïk, Stéphane
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700 1 _ |a Combarros, Onofre
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700 1 _ |a Berciano, José
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700 1 _ |a Uitterlinden, Andre G
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700 1 _ |a Collins, Steven J
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700 1 _ |a Budka, Herbert
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700 1 _ |a Brandel, Jean-Philippe
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700 1 _ |a Laplanche, Jean Louis
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700 1 _ |a Pocchiari, Maurizio
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700 1 _ |a Zerr, Inga
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700 1 _ |a Knight, Richard S G
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700 1 _ |a Will, Robert G
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700 1 _ |a van Duijn, Cornelia M
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773 1 8 |a 10.1371/journal.pone.0123654
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773 _ _ |a 10.1371/journal.pone.0123654
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856 7 _ |2 Pubmed Central
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