Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia
Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia
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DOI：
10.1093/brain/awz350
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发表时间：
2020-01-01
期刊：
影响因子：
14.5
通讯作者：
Singleton, Andrew B.
中科院分区：
文献类型：
--
作者：
Blauwendraat, Cornelis;Reed, Xylena;Singleton, Andrew B.
帕金森病是一种遗传复杂的疾病。多个基因已被证明有助于帕金森病的风险，目前已通过全基因组关联研究确定了90个独立的风险变体。到目前为止，许多基因（包括SNCA，LRRK 2和GBA）已被证明在频率和效应范围内包含变异性，从罕见的高度外显变异到具有小效应大小的常见风险等位基因。GBA的变异体，编码葡萄糖酸-艾糖苷酶，与路易体疾病如帕金森病和路易体痴呆有关。这些降低或消除酶活性的变体赋予疾病风险谱，从1.4倍到>10倍。该领域的一个突出问题是影响GBA相关疾病风险的其他遗传因素，以及这些因素是否与已知的帕金森病风险变体重叠。使用多个大型病例对照数据集，共计217165人（帕金森病22757例，帕金森病替代病例13431例，路易体痴呆622例，对照180355例），共确诊帕金森病1691例，路易体痴呆81例，711例代理病例和7624例对照具有GBA变体（p.E326K、p.T369M或p.N370S）。我们进行了一项全基因组关联研究，并分析了最新的帕金森病相关遗传风险评分，以检测遗传对GBA风险和发病年龄的影响。我们试图在两个独立的数据集中复制我们的发现，包括个人遗传学公司23和Me，Inc。和全基因组测序数据。我们的分析表明，帕金森病的遗传风险评分改变了疾病的风险，并降低了GBA变异携带者的发病年龄。值得注意的是，这种影响在所有测试的GBA风险变体中是一致的。对该信号的分析表明，与SNCA和CTSB（编码组织蛋白酶B）非常接近的变体是最显著的贡献者。CTSB基因座中的风险变体被鉴定为降低CTSB的mRNA表达。另外的分析表明GBA和CTSB之间可能存在遗传相互作用，并且显示GBA p.N370 S诱导的多能细胞衍生的神经元与对照相比具有降低的组织蛋白酶B表达。这些数据为GBA相关帕金森病风险和发病年龄的修改提供了遗传基础，尽管常见遗传变异的总贡献并不大。我们进一步证明了与溶酶体功能有关的基因的常见变异对GBA相关疾病风险的影响最大。此外，这些结果对选择GBA载体进行治疗干预具有意义。
Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocer-ebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23 and Me, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.