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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.
摘要：
朊病毒病是由朊病毒蛋白（PrP）的错误折叠和聚集引起的人类和动物的致命神经退行性疾病。哺乳动物朊病毒疾病受到强大的遗传控制，但除了PrP基因位点（PRNP）外，几乎没有危险因素。除了小样本的克雅氏病（CJD）外，还没有进行全基因组关联研究（GWAS）。我们进行了零星CJD(sCJD)的GWAS，变体CJD(vCJD)，医源性CJD,遗传性朊病毒病,尽管参加了太平间的盛宴，但库鲁和对库鲁的抵抗。质量控制后,在欧洲研究中,我们分析了2000个样本和6015个对照个体(由惠康信托病例控制协会和KORA-gen提供)的491032-511862个SNP.在每个地理和病因学组中进行了关联研究，然后进行了几项综合分析。在所有地理和病因组中，PRNP基因座与风险高度相关。该关联由rs1799990(PRNP密码子129)处的已知编码变异驱动。在所有人类朊病毒疾病的荟萃分析中，没有非PRNP基因座达到全基因组意义。在英国，ZBTB38-RASA2基因座的SNP与CJD相关（rs295301，P=3.13×10（-8）；OR，0.70），但这些SNP在德国sCJD或基于巴布亚新几内亚的测试中没有显示出关联的复制证据。CHN2基因中的SNP与vCJD相关[P=1.5×10(-7);比值比(OR),2.36],但不在英国sCJD(P=0.049；OR，1.24),在德国sCJD或PNG组中。在CJD的整体荟萃分析中，14个SNP相关(P<10(-5)；两个在PRNP，三个在ZBTB38-RASA2，九个在其他九个独立的非PRNP基因座），超出了偶然的预期。在其他神经退行性疾病的研究中，最近确定的全基因组意义上的基因座都没有显示出与朊病毒疾病相关的任何明确证据。关于常见的遗传变异，PRNP基因座很可能包含在人类朊病毒疾病中普遍起作用的唯一强危险因素。我们的数据与其他一些总体影响中等的风险位点最一致，这将需要进一步的遗传关联研究来提供明确的证据。
