title: Variants of PLCXD3 are not associated with variant or sporadic Creutzfeldt-Jakob disease in a large international study.
abstract: BACKGROUND
  Human prion diseases are relentlessly progressive neurodegenerative disorders which include sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). Aside from variants of the prion protein gene (PRNP) replicated association at genome-wide levels of significance has proven elusive. A recent association study identified variants in or near to the PLCXD3 gene locus as strong disease risk factors in multiple human prion diseases. This study claimed the first non-PRNP locus to be highly significantly associated with prion disease in genomic studies.
  
  
  METHODS
  A sub-study of a genome-wide association study with imputation aiming to replicate the finding at PLCXD3 including 129 vCJD and 2500 sCJD samples. Whole exome sequencing to identify rare coding variants of PLCXD3.
  
  
  RESULTS
  Imputation of relevant polymorphisms was accurate based on wet genotyping of a sample. We found no supportive evidence that PLCXD3 variants are associated with disease.
  
  
  CONCLUSIONS
  The marked discordance in vCJD genotype frequencies between studies, despite extensive overlap in vCJD cases, and the finding of Hardy-Weinberg disequilibrium in the original study, suggests possible reasons for the discrepancies between studies.
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Rubika
authors.initials: R
authors.lastname: Balendra
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: James
authors.initials: J
authors.lastname: Uphill
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Collinson
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Ronald
authors.initials: R
authors.lastname: Druyeh
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Adamson
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Holger
authors.initials: H
authors.lastname: Hummerich
authors.affiliation: Clinical Dementia Center, Department of Neurology, Georg-August University Göttingen, Göttingen, Germany.|German Center for Neurodegenerative Diseases, Gottingen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Zerr
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, 44060, USA.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. s.mead@prion.ucl.ac.uk.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
mesh_terms: D007562:Creutzfeldt-Jakob Syndrome / Q000175:diagnosis / Q000235:genetics*; D005091:Exons; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D005858:Germany; D006801:Humans; D015810:Linkage Disequilibrium; D054801:Phosphoinositide Phospholipase C / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D014481:United States
chemical_list: C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D054801:Phosphoinositide Phospholipase C; C000607434:phosphatidylinositol specific phospholipase C, human
keywords: Creutzfeldt-Jakob disease; Human prion diseases; PLCXD3