TY  - JOUR
AU  - Sanchez-Juan, Pascual
AU  - Bishop, Matthew T
AU  - Kovacs, Gabor G
AU  - Calero, Miguel
AU  - Aulchenko, Yurii S
AU  - Ladogana, Anna
AU  - Boyd, Alison
AU  - Lewis, Victoria
AU  - Ponto, Claudia
AU  - Calero, Olga
AU  - Poleggi, Anna
AU  - Carracedo, Ángel
AU  - van der Lee, Sven J
AU  - Ströbel, Thomas
AU  - Rivadeneira, Fernando
AU  - Hofman, Albert
AU  - Haïk, Stéphane
AU  - Combarros, Onofre
AU  - Berciano, José
AU  - Uitterlinden, Andre G
AU  - Collins, Steven J
AU  - Budka, Herbert
AU  - Brandel, Jean-Philippe
AU  - Laplanche, Jean Louis
AU  - Pocchiari, Maurizio
AU  - Zerr, Inga
AU  - Knight, Richard S G
AU  - Will, Robert G
AU  - van Duijn, Cornelia M
TI  - A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.
JO  - PLOS ONE
VL  - 10
IS  - 4
SN  - 1932-6203
CY  - San Francisco, California, US
PB  - PLOS
M1  - DZNE-2020-04231
SP  - e0123654
PY  - 2014
AB  - 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.
KW  - Case-Control Studies
KW  - Creutzfeldt-Jakob Syndrome: genetics
KW  - Genome-Wide Association Study: methods
KW  - Germany
KW  - Humans
KW  - Netherlands
KW  - Polymorphism, Single Nucleotide
KW  - Prion Proteins
KW  - Prions: genetics
KW  - Receptors, Metabotropic Glutamate: genetics
KW  - Signal Transduction
KW  - United Kingdom
KW  - PRNP protein, human (NLM Chemicals)
KW  - Prion Proteins (NLM Chemicals)
KW  - Prions (NLM Chemicals)
KW  - Receptors, Metabotropic Glutamate (NLM Chemicals)
KW  - metabotropic glutamate receptor 8 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25918841
C2  - pmc:PMC4412535
DO  - DOI:10.1371/journal.pone.0123654
UR  - https://pub.dzne.de/record/137909
ER  -