Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
Parkinsonism Relat Disord. 2014 Jan;20(1):93-8. doi: 10.1016/j.parkreldis.2013.10.001. Epub 2013 Oct 11.
Previous studies indicate that as many as six genes within the PARK10 region (RNF11, UQCRH, HIVEP3, EIF2B3, USP24, ELAVL4) might modify susceptibility or age at onset in Parkinson's disease (PD).
We sought to identify new PD susceptibility genes and to validate previously nominated candidate genes within the PARK10 region using a two-stage design. We used data from a large, publicly-available genome-wide association study (GWAS) in the discovery stage (n = 2000 cases and 1986 controls) and data from three independent studies for the replication stage (total n = 2113 cases and 2095 controls). Marker density was increased by imputation using HapMap 3 and 1000 Genomes reference panels, and over 40,000 single nucleotide polymorphisms (SNPs) were used in the final analysis. The association between each SNP and PD was modeled using logistic regression with an additive allele dosage effect and adjusted for sex, age, and axes of geographical variation.
Although the discovery stage yielded promising findings for SNPs in several novel genes, including DAB1, none of the results were validated in the replication stage. Furthermore, in meta-analyses across all datasets no genes within PARK10 reached significance after accounting for multiple testing.
Our results suggest that common variation in the PARK10 region is not associated with PD risk. However, additional studies are needed to assess the role of PARK10 in modifying age at onset and to determine whether rare variants in this region might affect PD susceptibility.
先前的研究表明，PARK10 区域内多达 6 个基因（RNF11、UQCRH、HIVEP3、EIF2B3、USP24、ELAVL4）可能会改变帕金森病（PD）的易感性或发病年龄。
我们试图通过两阶段设计来确定新的 PD 易感基因，并验证 PARK10 区域内先前提名的候选基因。我们在发现阶段（n=2000 例病例和 1986 例对照）使用了来自大型公共全基因组关联研究（GWAS）的数据，在复制阶段（总 n=2113 例病例和 2095 例对照）使用了三个独立研究的数据。使用 HapMap 3 和 1000 基因组参考面板进行了单核苷酸多态性（SNP）的推断，增加了标记密度，最终分析中使用了超过 40000 个 SNP。使用逻辑回归模型，以加性等位基因剂量效应来模拟每个 SNP 与 PD 之间的关联，并对性别、年龄和地理变异轴进行了调整。
尽管在发现阶段，几个新基因中的 SNP 显示出有希望的结果，包括 DAB1，但在复制阶段均未得到验证。此外，在所有数据集的荟萃分析中，在考虑了多次检验后，PARK10 内没有任何基因达到显著水平。
我们的研究结果表明，PARK10 区域内的常见变异与 PD 风险无关。然而，需要进一步的研究来评估 PARK10 在改变发病年龄中的作用，并确定该区域内的稀有变异是否会影响 PD 的易感性。
