A two-stage meta-analysis identifies several new loci for Parkinson's disease.
A two-stage meta-analysis identifies several new loci for Parkinson's disease.
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DOI：
10.1371/journal.pgen.1002142
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发表时间：
2011-06
期刊：
影响因子：
4.5
通讯作者：
Wellcome Trust Case Control Consortium 2 (WTCCC2)
中科院分区：
文献类型：
--
作者：
International Parkinson's Disease Genomics Consortium (IPDGC);Wellcome Trust Case Control Consortium 2 (WTCCC2)
国际帕金森病基因组学联盟(IPDGC)先前对12,386例帕金森病患者和21,026名对照进行的全基因组关联(GWA)荟萃分析发现或确认了11个帕金森病(PD)基因座。这项分两个阶段的IPDGC研究的第一个分析集中在第一阶段GWA扫描中通过全基因组意义的一组基因座上。然而，第二阶段基因分型阵列，免疫芯片，包括一组更大的1,920个基于GWA分析选择的SNPs。在这里，我们分析了这组1,920个−，并发现了另外5个PD风险基因座(组合p<；5×10 SNP 10、PARK16/1q32、STX1B/16p11、FGF20/8p22、STBd1/4q21和GPNMB/7p15)。先前的关联研究(PARK16/1q32，FGF20/8p22)提出了这五个基因座中的两个，这项研究进一步支持了这些发现。使用一组死后脑样本的基因表达(n = 399)和甲基化(n = 292)的数据，我们确定了PARK16/1q32、GPNMB/7p15和STX1B/16p11基因座与帕金森病风险变异相关的甲基化和表达变化，从而提出了这些风险基因座潜在的分子机制和候选基因。这篇论文描述了迄今为止最大的帕金森氏病病例对照分析，包括超过12,000个病例和21,000个对照的组合样本集。将我们的发现与3000多个病例和29,000个对照的独立复制数据集相结合后，我们发现了除了先前联盟研究中发现的11个基因座之外，还有另外5个PD风险基因座。这项成功的研究进一步证明了GWA扫描实验设计的力量，即使在帕金森氏症等复杂疾病的背景下，也能找到导致疾病风险的新基因座。这些新发现为帕金森病的病因提供了洞察力，并将促进对其发病机制的更好理解。
A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p<5×10−10, PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n = 399) and methylation (n = 292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci. This paper describes the largest case-control analysis of Parkinson's disease to date, with a combined sample set of over 12,000 cases and 21,000 controls. After combining our findings with an independent replication dataset of more than 3,000 cases and 29,000 controls, we found five additional PD risk loci in addition to the 11 loci previously identified in earlier consortium efforts. This successful study further demonstrates the power of the GWA scan experimental design to find new loci contributing to disease risk, even in the context of complex disorders like Parkinson's disease. These new findings provide insights into the etiology of PD and will promote a better understanding of its pathogenesis.
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