Rare structural genetic variation in human prion diseases.
Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfolding of prion protein. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other variants have been suggested to confer risk in the most common type, sporadic Creutzfeldt-Jakob disease (sCJD) or in the acquired prion diseases. Large and rare copy number variants (CNVs) are known to confer risk in several related disorders including Alzheimer's disease (at APP), schizophrenia, epilepsy, mental retardation, and autism. Here, we report the first genome-wide analysis for CNV-associated risk using data derived from a recent international collaborative association study in sCJD (n = 1147 after quality control) and publicly available controls (n = 5427). We also investigated UK patients with variant Creutzfeldt-Jakob disease (n = 114) and elderly women from the Eastern Highlands of Papua New Guinea who proved highly resistant to the epidemic prion disease kuru, who were compared with healthy young Fore population controls (n = 395). There were no statistically significant alterations in the burden of CNVs >100, >500, or >1000 kb, duplications, or deletions in any disease group or geographic region. After correction for multiple testing, no statistically significant associations were found. A UK blood service control sample showed a duplication CNV that overlapped PRNP, but these were not found in prion disease. Heterozygous deletions of a 3' region of the PARK2 gene were found in 3 sCJD patients and no controls (p = 0.001, uncorrected). A cell-based prion infection assay did not provide supportive evidence for a role for PARK2 in prion disease susceptibility. These data are consistent with a modest impact of CNVs on risk of late-onset neurologic conditions and suggest that, unlike APP, PRNP duplication is not a causal high-risk mutation.
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
Ana
A
Lukic
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
James
J
Uphill
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
Craig A
CA
Brown
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
John
J
Beck
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
Mark
M
Poulter
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
Tracy
T
Campbell
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
Gary
G
Adamson
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
Holger
H
Hummerich
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
Jerome
J
Whitfield
Department of Neurology, Georg-August University Göttingen, Göttingen, Germany; German Center for Neurodegenrative Diseases (DZNE), Gottingen, Germany.
Claudia
C
Ponto
Department of Neurology, Georg-August University Göttingen, Göttingen, Germany; German Center for Neurodegenrative Diseases (DZNE), Gottingen, Germany.
Inga
I
Zerr
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
Sarah E
SE
Lloyd
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
John
J
Collinge
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK. Electronic address: s.mead@prion.ucl.ac.uk.
Simon
S
Mead
D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D002478:Cells, Cultured; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007729:Kuru / Q000235:genetics; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D017096:Prion Diseases / Q000235:genetics*; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics*; D012306:Risk; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D020413:3' Untranslated Regions; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
CJD; CNV; GWAS; Kuru; Prion