A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.
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.
Neurology Department, University Hospital "Marqués de Valdecilla". Instituto de Investigación "Marqués de Valdecilla" IDIVAL and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED). Santander, Spain.
Pascual
P
Sanchez-Juan
The National Creutzfeldt-Jakob disease Research and Surveillance Unit, University of Edinburgh, United Kingdom.
Matthew T
MT
Bishop
Institute of Neurology, Medical University Vienna, Vienna, Austria.
Gabor G
GG
Kovacs
Chronic Disease Programme and CIBERNED. Carlos III Institute of Health. Madrid. Spain; Alzheimer Disease Research Unit, CIEN Foundation, Carlos III Institute of Health, Alzheimer Center Reina Sofia Foundation, Madrid, Spain.
Miguel
M
Calero
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands; Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia; Novosibirsk State University, Novosibirsk, Russia.
Yurii S
YS
Aulchenko
Department of Cell Biology and Neurosciences Instituto Superiore di Sanità, Roma, Italy.
Anna
A
Ladogana
Department of Pathology, The University of Melbourne, Parkville, 3010, Australia.
Alison
A
Boyd
Department of Pathology, The University of Melbourne, Parkville, 3010, Australia.
Victoria
V
Lewis
Department of Neurology, Clinical Dementia Centre, University Medical Center and German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen, Germany.
Claudia
C
Ponto
Chronic Disease Programme and CIBERNED. Carlos III Institute of Health. Madrid. Spain.
Olga
O
Calero
Department of Cell Biology and Neurosciences Instituto Superiore di Sanità, Roma, Italy.
Anna
A
Poleggi
Fundación Pública Galega de Medicina Xenómica, CIBERER, Grupo de Medicina Xenómica-Universidad de Santiago de Compostela, Santiago de Compostela, Spain; Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, KSA.
Ángel
Á
Carracedo
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
Sven J
SJ
van der Lee
Institute of Neurology, Medical University Vienna, Vienna, Austria.
Thomas
T
Ströbel
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
Fernando
F
Rivadeneira
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
Albert
A
Hofman
Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, and Inserm, U 1127, and CNRS UMR 7225, and ICM, F-75013, Paris, France; AP-HP, Hôpital de la Pitié Salpêtrière, Cellule Nationale de Référence des maladies de Creutzfeldt-Jakob, F-75013, Paris, France.
Stéphane
S
Haïk
Neurology Department, University Hospital "Marqués de Valdecilla". Instituto de Investigación "Marqués de Valdecilla" IDIVAL and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED). Santander, Spain.
Onofre
O
Combarros
Neurology Department, University Hospital "Marqués de Valdecilla". Instituto de Investigación "Marqués de Valdecilla" IDIVAL and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED). Santander, Spain.
José
J
Berciano
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
Andre G
AG
Uitterlinden
Department of Pathology, The University of Melbourne, Parkville, 3010, Australia.
Steven J
SJ
Collins
Institute of Neurology, Medical University Vienna, Vienna, Austria.
Herbert
H
Budka
Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, and Inserm, U 1127, and CNRS UMR 7225, and ICM, F-75013, Paris, France; AP-HP, Hôpital de la Pitié Salpêtrière, Cellule Nationale de Référence des maladies de Creutzfeldt-Jakob, F-75013, Paris, France.
Jean-Philippe
JP
Brandel
Service de biochimie et biologie moleculaire, Laboratoire associé au CNR "ATNC", Hôpital Lariboisiére, AP-HP, Paris, France.
Jean Louis
JL
Laplanche
Department of Cell Biology and Neurosciences Instituto Superiore di Sanità, Roma, Italy.
Maurizio
M
Pocchiari
Department of Neurology, Clinical Dementia Centre, University Medical Center and German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen, Germany.
Inga
I
Zerr
The National Creutzfeldt-Jakob disease Research and Surveillance Unit, University of Edinburgh, United Kingdom.
Richard S G
RS
Knight
The National Creutzfeldt-Jakob disease Research and Surveillance Unit, University of Edinburgh, United Kingdom.
Robert G
RG
Will
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
Cornelia M
CM
van Duijn
D016022:Case-Control Studies; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005858:Germany; D006801:Humans; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics*; D015398:Signal Transduction; D006113:United Kingdom
C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D018094:Receptors, Metabotropic Glutamate; C111435:metabotropic glutamate receptor 8