Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility.

中文翻译：

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帕金森病中溶酶体贮积症基因变异负担过重。


葡萄糖脑苷脂酶基因 (GBA) 的突变会导致戈谢病，也是帕金森病的潜在危险因素。我们检查了其他溶酶体贮积症基因变异的遗传负担是否与帕金森病易感性更广泛相关。序列核关联测试用于询问 54 个溶酶体贮积症基因之间的变异负担，利用来自 1156 名帕金森病病例和 1679 名对照受试者的全外显子组测序数据。我们发现，罕见的、可能具有破坏性的溶酶体贮积症基因变异与帕金森病风险相关。排除 GBA 后，关联信号是稳健的，并且在两个独立的复制队列中获得了一致的结果，包括采用全外显子组测序的 436 例病例和 169 例对照，以及采用全外显子组基因分型的另外 6713 例病例和 5964 例对照。在旨在突出驱动聚合信号的特定基因的二次分析中，我们确认了 GBA 和 SMPD1 位点的关联，并新发现 CTSD、SLC17A5 和 ASAH1 作为候选帕金森病易感基因。在我们的发现队列中，大多数帕金森病病例 (56%) 的溶酶体贮积症基因中至少有一种假定的破坏性变异，21% 携带多个等位基因。我们的结果强调了几个有希望的新易感位点，并强调了溶酶体机制在帕金森病发病机制中的重要性。我们认为，多种基因打击可能联合作用，降低溶酶体功能，从而增强帕金森病的易感性。