Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP

Abstract

Prion diseases are fatal neurodegenerative diseases of humans and animals caused by the misfolding and aggregation of prion protein (PrP). Mammalian prion diseases are under strong genetic control but few risk factors are known aside from the PrP gene locus (PRNP). No genome-wide association study (GWAS) has been done aside from a small sample of variant Creutzfeldt-Jakob disease (CJD). We conducted GWAS of sporadic CJD (sCJD), variant CJD (vCJD), iatrogenic CJD, inherited prion disease, kuru and resistance to kuru despite attendance at mortuary feasts. After quality control, we analysed 2000 samples and 6015 control individuals (provided by the Wellcome Trust Case Control Consortium and KORA-gen) for 491032-511862 SNPs in the European study. Association studies were done in each geographical and aetiological group followed by several combined analyses. The PRNP locus was highly associated with risk in all geographical and aetiological groups. This association was driven by the known coding variation at rs1799990 (PRNP codon 129). No non-PRNP loci achieved genome-wide significance in the meta-analysis of all human prion disease. SNPs at the ZBTB38-RASA2 locus were associated with CJD in the UK (rs295301, P = 3.13 × 10(-8); OR, 0.70) but these SNPs showed no replication evidence of association in German sCJD or in Papua New Guinea-based tests. A SNP in the CHN2 gene was associated with vCJD [P = 1.5 × 10(-7); odds ratio (OR), 2.36], but not in UK sCJD (P = 0.049; OR, 1.24), in German sCJD or in PNG groups. In the overall meta-analysis of CJD, 14 SNPs were associated (P < 10(-5); two at PRNP, three at ZBTB38-RASA2, nine at nine other independent non-PRNP loci), more than would be expected by chance. None of the loci recently identified as genome-wide significant in studies of other neurodegenerative diseases showed any clear evidence of association in prion diseases. Concerning common genetic variation, it is likely that the PRNP locus contains the only strong risk factors that act universally across human prion diseases. Our data are most consistent with several other risk loci of modest overall effects which will require further genetic association studies to provide definitive evidence.

The Genetics of Susceptibility to Variant Creutzfeldt-Jakob Disease

“…Many of these polymorphic sites, however, have not been evaluated to the large extent the 129 polymorphism has. Indeed, in a recent study with a larger cohort of 2,000 human prion patients, no SNPs within PRNP other than at codon 129 were determined to be significant [36]. Further work must be performed to determine the prevalence and potential role of PRNP locus SNPs, but it seems likely that they may have a modest overall effect.…”

Rare structural genetic variation in human prion diseases

“…Homozygous genotypes at codon 129 also strongly associate with sporadic CJD [33], iatrogenic CJD [7] and early age of onset in inherited prion disease (IPD) [34] and kuru [5,9,32]. About a third of the European population exposed to BSE are homozygous for methionine at PRNP codon 129, whilst only around 220 individuals have developed vCJD to date, there is therefore considerable potential for other strong genetic susceptibility factors [29,30,36]. Indeed, the presence of non-PRNP genetic factors has been supported by several non-human studies of mammalian prion disease [20,23].…”

“…Several large-scale association studies have reported a role for large CNVs in susceptibility to several human conditions including idiopathic epilepsy, attention deficit hyperactivity disorder, schizophrenia, bipolar disorder, mental retardation, autism, and Alzheimer's disease [1,6,13,14,25,26,40] [2,3,19,21,22,29,30,36]. As a generalisation, few common structural genetic variations are risk factors in common diseases [10], whereas several rare CNVs, including whole or partial gene deletions and/or duplications are known to be major risk factors and/or dominantly inherited disease causing mutations in neurodegenerative diseases [1,13,14,25,26,35,40].…”

“…As a generalisation, few common structural genetic variations are risk factors in common diseases [10], whereas several rare CNVs, including whole or partial gene deletions and/or duplications are known to be major risk factors and/or dominantly inherited disease causing mutations in neurodegenerative diseases [1,13,14,25,26,35,40]. Here we used genotyping data from a recent genome-wide association study using Illumina 660 bead arrays [30], and publicly available European control data, to identify large and rare CNVs that might not have been mapped by linkage disequilibrium with neighbouring SNPs and perform association studies. We looked to discover CNVs in novel risk genes and test hypotheses based on candidate genes suggested from association studies in prion disease and related conditions.…”

The identification of candidate genes and SNP markers for classical bovine spongiform encephalopathy susceptibility

“…Additionally, genome wide association studies in humans have identified other loci of modest overall effect as research targets. 23 The objective of this study was to refine previously identified regions associated with BSE susceptibility and to identify positional candidate genes and genetic variation that may be involved with the progression of classical BSE.…”