title: Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study.
abstract: BACKGROUND
  Human and animal prion diseases are under genetic control, but apart from PRNP (the gene that encodes the prion protein), we understand little about human susceptibility to bovine spongiform encephalopathy (BSE) prions, the causal agent of variant Creutzfeldt-Jakob disease (vCJD).
  
  
  METHODS
  We did a genome-wide association study of the risk of vCJD and tested for replication of our findings in samples from many categories of human prion disease (929 samples) and control samples from the UK and Papua New Guinea (4254 samples), including controls in the UK who were genotyped by the Wellcome Trust Case Control Consortium. We also did follow-up analyses of the genetic control of the clinical phenotype of prion disease and analysed candidate gene expression in a mouse cellular model of prion infection.
  
  
  RESULTS
  The PRNP locus was strongly associated with risk across several markers and all categories of prion disease (best single SNP [single nucleotide polymorphism] association in vCJD p=2.5 x 10(-17); best haplotypic association in vCJD p=1 x 10(-24)). Although the main contribution to disease risk was conferred by PRNP polymorphic codon 129, another nearby SNP conferred increased risk of vCJD. In addition to PRNP, one technically validated SNP association upstream of RARB (the gene that encodes retinoic acid receptor beta) had nominal genome-wide significance (p=1.9 x 10(-7)). A similar association was found in a small sample of patients with iatrogenic CJD (p=0.030) but not in patients with sporadic CJD (sCJD) or kuru. In cultured cells, retinoic acid regulates the expression of the prion protein. We found an association with acquired prion disease, including vCJD (p=5.6 x 10(-5)), kuru incubation time (p=0.017), and resistance to kuru (p=2.5 x 10(-4)), in a region upstream of STMN2 (the gene that encodes SCG10). The risk genotype was not associated with sCJD but conferred an earlier age of onset. Furthermore, expression of Stmn2 was reduced 30-fold post-infection in a mouse cellular model of prion disease.
  
  
  CONCLUSIONS
  The polymorphic codon 129 of PRNP was the main genetic risk factor for vCJD; however, additional candidate loci have been identified, which justifies functional analyses of these biological pathways in prion disease.
authors.affiliation: Medical Research Council Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.forename: Mark
authors.initials: M
authors.lastname: Poulter
authors.forename: James
authors.initials: J
authors.lastname: Uphill
authors.forename: John
authors.initials: J
authors.lastname: Beck
authors.forename: Jerome
authors.initials: J
authors.lastname: Whitfield
authors.forename: Thomas E F
authors.initials: TE
authors.lastname: Webb
authors.forename: Tracy
authors.initials: T
authors.lastname: Campbell
authors.forename: Gary
authors.initials: G
authors.lastname: Adamson
authors.forename: Pelagia
authors.initials: P
authors.lastname: Deriziotis
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
authors.forename: Holger
authors.initials: H
authors.lastname: Hummerich
authors.forename: Claudio
authors.initials: C
authors.lastname: Verzilli
authors.forename: Michael P
authors.initials: MP
authors.lastname: Alpers
authors.forename: John C
authors.initials: JC
authors.lastname: Whittaker
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D002877:Chromosomes, Human / Q000235:genetics; D007562:Creutzfeldt-Jakob Syndrome / Q000453:epidemiology* / Q000235:genetics*; D004247:DNA / Q000235:genetics; D003627:Data Interpretation, Statistical; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007729:Kuru / Q000453:epidemiology; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D010219:Papua New Guinea / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics; D011786:Quality Control; D012307:Risk Factors; D050777:Stathmin; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D008565:Membrane Proteins; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; C063314:STMN2 protein, human; D050777:Stathmin; D004247:DNA