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@ARTICLE{SanchezJuan:137909,
author = {Sanchez-Juan, Pascual and Bishop, Matthew T and Kovacs,
Gabor G and Calero, Miguel and Aulchenko, Yurii S and
Ladogana, Anna and Boyd, Alison and Lewis, Victoria and
Ponto, Claudia and Calero, Olga and Poleggi, Anna and
Carracedo, Ángel and van der Lee, Sven J and Ströbel,
Thomas and Rivadeneira, Fernando and Hofman, Albert and
Haïk, Stéphane and Combarros, Onofre and Berciano, José
and Uitterlinden, Andre G and Collins, Steven J and Budka,
Herbert and Brandel, Jean-Philippe and Laplanche, Jean Louis
and Pocchiari, Maurizio and Zerr, Inga and Knight, Richard S
G and Will, Robert G and van Duijn, Cornelia M},
title = {{A} genome wide association study links glutamate receptor
pathway to sporadic {C}reutzfeldt-{J}akob disease risk.},
journal = {PLOS ONE},
volume = {10},
number = {4},
issn = {1932-6203},
address = {San Francisco, California, US},
publisher = {PLOS},
reportid = {DZNE-2020-04231},
pages = {e0123654},
year = {2014},
abstract = {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.},
keywords = {Case-Control Studies / Creutzfeldt-Jakob Syndrome: genetics
/ Genome-Wide Association Study: methods / Germany / Humans
/ Netherlands / Polymorphism, Single Nucleotide / Prion
Proteins / Prions: genetics / Receptors, Metabotropic
Glutamate: genetics / Signal Transduction / United Kingdom /
PRNP protein, human (NLM Chemicals) / Prion Proteins (NLM
Chemicals) / Prions (NLM Chemicals) / Receptors,
Metabotropic Glutamate (NLM Chemicals) / metabotropic
glutamate receptor 8 (NLM Chemicals)},
cin = {AG Zerr},
ddc = {610},
cid = {I:(DE-2719)1440011-1},
pnm = {344 - Clinical and Health Care Research (POF3-344)},
pid = {G:(DE-HGF)POF3-344},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:25918841},
pmc = {pmc:PMC4412535},
doi = {10.1371/journal.pone.0123654},
url = {https://pub.dzne.de/record/137909},
}