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Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study

Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study,Simon Mead,Mark Poulter,James Uphill,John Beck,Thomas E F

Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study   (Citations: 16)
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Simon Mead, Mark Poulter, James Uphill, John Beck, Thomas E F Webb, Tracy Campbell, Gary Adamson, Sarah J Tabrizi, Holger Hummerich, Claudio Verzilli, Michael P Alpers, John C Whittakerhttp://academic.research.microsoft.com/io.ashx?type=5&id=5669398&selfId1=0&selfId2=0&maxNumber=12&query=
Methods We did a genome-wide association study of the risk of vCJD and tested for replication of our fi ndings in samples from many categories of human prion disease (929 samples) and control samples from the UK and P apua New Guinea (4254 samples), including controls in the UK who were genotyped by the W ellcome 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. Findings 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=2·5×10 - ¹⁷; best haplotypic association in vCJD p=1×10 - 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 signifi cance (p=1·9×10 - 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=5·6×10 - ⁵), kuru incubation time (p=0·017), and resistance to kuru (p=2·5×10 - 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.
Published in 2009.
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