Elucidation of molecular mechanisms of Parkinson disease based on comprehensive nucleotide sequence analysis of glucocerebrosidase gene.

本研究旨在阐明散发性帕金森病的易感基因。对534例日本散发性帕金森病患者和544名日本健康对照者进行了GBA（葡萄糖脑苷酶基因）的全面重测序分析。我们发现，GBA杂合变异体在帕金森病中的发生率为9.4%，显著高于对照组（0.37%），优势比为28.0 （95% CI: 4.3-238.3, p=6.9X10^<-14>）。我们进一步开展了国际合作，探讨GBA的杂合变异体是否与种族无关地赋予帕金森病如此高的风险。我们证实，GBA的杂合变异体与种族无关，具有帕金森病的高风险。这些结果强烈表明，全面的重测序分析是鉴定罕见变异的必要条件。为了能够对大型数据集进行全面的重测序，我们应用了下一代测序仪来分析汇集的DNA。我们证明，我们可以使用由6个样本组成的基因组DNA池灵敏而准确地确定变异的等位基因频率。

This study aimed to elucidate susceptibility genes for sporadic Parkinson disease. Comprehensive resequencing analysis of GBA (glucocerebrosidase gene) has been conducted using 534 Japanese cases of sporadic Parkinson disease and 544 Japanese healthy controls. We found that the frequency of cases of Parkinson disease with heterozygous variants of GBA was 9.4%, which was significantly more frequent than that of controls (0.37%) with the odds ratio of 28.0 (95% CI : 4.3-238.3, p=6.9X10^<-14>). We furthermore conducted international collaboration to explore whether heterozygous variants of GBA confer such a strong risk for Parkinson disease irrespective of ethnicity. We confirmed that heterozygous variants of GBA confers a strong risk for Parkinson disease irrespective of ethnicity. These results strongly indicate that comprehensive resequencing analysis is necessary to identify rare variants. To enable comprehensive resequencing of large data sets, we applied next generation sequencers to analyze pooled DNA. We demonstrated that we can sensitively and accurately determine the allele frequencies of variants using pooled genomic DNA consisting of 6 samples.