High-resolution whole-genome association study of Parkinson disease
High-resolution whole-genome association study of Parkinson disease
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DOI：
10.1086/496902
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发表时间：
2005-11-01
影响因子：
9.8
通讯作者：
Ballinger, DG
中科院分区：
文献类型：
--
作者：
Maraganore, DM;de Andrade, M;Ballinger, DG
我们进行了一个两层，全基因组关联研究帕金森病（PD）。对于第1层，我们在443对与PD不一致的兄弟姐妹中单独对198，345个均匀间隔和信息性单核苷酸多态性（SNP）进行基因分型。对于第2a层，我们在332个匹配的病例无关对照对中分别对1，793个PD相关SNP（第1层）和300个P <0.01的基因组对照SNP进行基因分型。我们在第1层和第2层样本中确定了11个与PD相关的SNP（P <0.01），并且具有相同的作用方向。对于这些SNP，我们将来自病例未受影响的同胞对（第1层）和病例无关的对照对（第2层）样本的P <0.01数据结合起来，并采用同胞传递/不平衡检验的自由化来计算比值比、95%置信区间和P值。脑信号蛋白5A基因内的SNP（SEMA 5A）具有最低的组合P值（P = 7.62 x 10（-6））。该基因编码的蛋白质在神经发生和神经元凋亡中起着重要作用，这与现有的关于PD发病机制的假设一致。第二个SNP标记PARK 11迟发性PD易感性位点（P = 1.70 x 10（-5））。在第2b层中，我们还选择了在第1层中具有边缘显著性（P < .05）的额外SNP进行基因分型，但测试了有关PD易感性的先验生物学和遗传假设（SNP）。在对第1层和第2b层组合数据的分析中，具有最低n p 941 P值（P = 9.07 x 10（-6）; P = 2.96 x 10（-5））的两个SNP标记PARK 10晚发型PD易感性基因座。跨人群的独立复制将阐明由这些SNP标记的基因组位点在赋予PD易感性中的作用。
We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms ( SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs ( in tier 1) and 300 P < .01 genomic control SNPs in 332 matched case - unrelated control pairs. We identified 11 SNPs that were associated with PD (P < .01) in both tier 1 and tier 2 samples and had the same direction of effect. For these SNPs, we combined P < .01 data from the case-unaffected sibling pair (tier 1) and case - unrelated control pair (tier 2) samples and employed a liberalization of the sibling transmission/disequilibrium test to calculate odds ratios, 95% confidence intervals, and P values. A SNP within the semaphorin 5A gene (SEMA5A) had the lowest combined P value (P = 7.62 x 10(-6)). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which is consistent with existing hypotheses regarding PD pathogenesis. A second SNP tagged the PARK11 late-onset PD susceptibility locus (P = 1.70 x 10(-5)). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P < .05) in tier 1 but that tested a priori biological and genetic hypotheses regarding susceptibility to PD (SNPs). In analysis of the combined tier 1 and tier 2b data, the two SNPs with the lowest n p 941 P values (P = 9.07 x 10(-6); P = 2.96 x 10(-5) ) tagged the PARK10 late-onset PD susceptibility locus. Independent replication across populations will clarify the role of the genomic loci tagged by these SNPs in conferring PD susceptibility.