Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP
Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP
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DOI：
10.1093/hmg/ddr607
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发表时间：
2012-04-15
影响因子：
3.5
通讯作者：
Collinge, John
中科院分区：
文献类型：
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作者：
Mead, Simon;Uphill, James;Collinge, John
朊病毒病是由朊病毒蛋白（PrP）错误折叠和聚集引起的人类和动物致命的神经退行性疾病。哺乳动物朊病毒疾病受到强有力的遗传控制，但除了 PrP 基因位点 (PRNP) 之外，已知的危险因素很少。除了变异型克雅氏病 (CJD) 的小样本外，尚未进行全基因组关联研究 (GWAS)。我们对散发性克雅氏病 (sCJD)、变异型克雅氏病 (vCJD)、医源性克雅氏病、遗传性朊病毒病、库鲁病以及参加太平间盛宴的库鲁病耐药性进行了 GWAS。经过质量控制后，我们分析了欧洲研究中的 2000 个样本和 6015 个对照个体（由 Wellcome Trust Case Control Consortium 和 KORA-gen 提供）的 491032-511862 个 SNP。在每个地理和病因学组中进行关联研究，然后进行多项组合分析。 PRNP 基因座与所有地理和病因学群体的风险高度相关。这种关联是由 rs1799990（PRNP 密码子 129）的已知编码变异驱动的。在所有人类朊病毒病的荟萃分析中，没有非 PRNP 位点达到全基因组显着性。 ZBTB38RASA2 位点的 SNP 在英国与克雅氏病相关（rs295301，P 3.13 10(8)；OR，0.70），但这些 SNP 在德国 sCJD 或巴布亚新几内亚的测试中没有显示关联的复制证据。 CHN2 基因中的 SNP 与 vCJD 相关 [P 1.5 10(7)；比值比 (OR), 2.36]，但在英国 sCJD 中则不然（P 0.049；OR，1.24），在德国 sCJD 或巴布亚新几内亚组中则不然。在克雅氏病的总体荟萃分析中，有 14 个 SNP 相关（P 10(5)；两个位于 PRNP，三个位于 ZBTB38RASA2，九个位于其他 9 个独立的非 PRNP 位点），比偶然预期的要多。最近在其他神经退行性疾病研究中发现的在全基因组范围内具有重要意义的基因座均未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 基因座可能包含唯一在人类朊病毒疾病中普遍起作用的强风险因素。我们的数据与其他几个总体影响不大的风险位点最为一致，这需要进一步的遗传关联研究来提供明确的证据。
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 CreutzfeldtJakob 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 ZBTB38RASA2 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 ZBTB38RASA2, 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.