Genetic evidence for ubiquitin-specific proteases USP24 and USP40 as candidate genes for late-onset Parkinson disease
Genetic evidence for ubiquitin-specific proteases USP24 and USP40 as candidate genes for late-onset Parkinson disease
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DOI：
10.1002/humu.20382
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发表时间：
2006-10-01
期刊：
影响因子：
3.9
通讯作者：
Grupe, Andrew
中科院分区：
文献类型：
--
作者：
Li, Yonghong;Schrodi, Steven;Grupe, Andrew
连锁研究已经确定了1号和2号染色体上迟发性帕金森病（PD）的易感区域，但尚未明确确定特定的遗传变异。在这里，我们报告的结果，病例对照研究，以确定疾病相关的单核苷酸多态性（SNPs）在这些位点。在我们研究的初始阶段，我们对泛素特异性蛋白酶24（USP 24）中两个假定的功能性SNP进行了基因分型，这是1号染色体连锁区内的生物学候选基因，并在224例PD病例和186例匹配对照的样本集中用43个SNP扫描了2号染色体连锁峰。两个USP 24 SNP均与疾病风险显著相关（rs 1165222：T > C，p.Thr195ILe p = 0.0037，rs 13312：C > G，3 '-非翻译区的SNP p = 0.037），USP 40中的一个标记rs 1048603：C > T，p.Arg1123Cys在2号染色体扫描中具有显著性（p = 0.038）。对这些初始标记周围区域的进一步基因分型使我们鉴定出19个具有强疾病关联的额外SNP。在第二阶段，我们对另外110例病例和162例对照中的22个显著标记进行了基因分型，这些标记与部分初始样本集（201例病例和149例对照）一起构成了311个年龄和性别匹配的病例对照对的扩展样本集。21个标志物在扩展的样品组中是显著的（最显著的等位基因p值：rs 287235：1号染色体上的C > G为0.0006，rs 838552：2号染色体上的T > C为0.005），并且USP 24中的6个SNP在保守调整测试27个标志物后保持显著（p（Bonferroni）= 0.017-0-049）。这是不可能的，人口分层有助于这一发现，因为人口分层是无法检测到在我们的样本集使用78个空标记。我们的数据表明，USP 24和USP 40中的遗传变异影响迟发性PD的风险，这与泛素化途径在PD病因学中的预测作用一致。
Linkage studies have defined susceptibility regions for late onset Parkinson disease (PD) on chromosomes 1 and 2, but specific genetic variants have not been definitively identified. Here we report the results of a case-control study to identify disease-associated single nucleotide polymorphisms (SNPs) in these loci. In the initial phase of our study, we genotyped two putative functional SNPs in ubiquitin, specific protease 24 (USP24), a biological candidate gene within the chromosome 1 linkage region, and scanned the chromosome 2 linkage peak with 43 SNPs in a sample set of 224 PD cases and 186 matched controls. Both USP24 SNPs were significantly associated with disease risk (p = 0.0037 for rs 1165222:T > C, p.Thr195ILe, and p = 0.037 for rs 13312:C > G, a SNP in the 3'-untranslated region), and one marker, rs1048603:C > T, p.Arg1123Cys, in USP40 was significant from the chromosome 2 scan (p = 0.038). Further genotyping of the region surrounding these initial markers led us to identify 19 additional SNPs with strong disease association. In the second phase, we genotyped the 22 significant markers in an additional 110 cases and 162 controls, which together with part of the initial sample set (201 cases and 149 controls) constitute an expanded sample set of 311 age- and gender-matched case-control pairs. Twenty-one markers were significant in the expanded sample set (most significant allelic p-value: 0.0006 for rs287235:C > G on chromosome 1, and 0.005 for rs838552:T > C on chromosome 2), and six SNPs in USP24 remained significant after conservatively adjusting for testing 27 markers (p(Bonferroni) = 0.017-0-049). It is unlikely that population stratification contributed to this finding, as population stratification was undetectable in our sample set using 78 null markers. Our data suggest that genetic variants in USP24 and USP40 affect the risk for late,onset PD, which is consistent with the predicted role of the ubiquitination pathway in PD etiology.